Substituted naphthyridine and quinoline compounds as MAO inhibitors

ABSTRACT

The invention provides a chemical entity of Formula (I) 
                         
wherein R 1 , R 2 , R 3 , Y, and n have any of the values described herein and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies, detection and imaging techniques, and radioactive treatments; and therapies, including inhibiting MAO, and MAO-B selectively, enhancing neuronal plasticity, treating neurological disorders, providing neuroprotection, treating a cognitive impairment associated with a CNS disorder, enhancing the efficiency of cognitive and motor training, providing neurorecovery and neurorehabilitation, enhancing the efficiency of non-human animal training protocols, and treating peripheral disorders (including obesity, diabetes, and cardiometabolic disorders) and their associated co-morbidities.

INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS

Any and all priority claims identified in the Application Data Sheet, orany correction thereto, are hereby incorporated by reference under 37CFR 1.57. For example, this application claims the benefit under 35U.S.C. §119(e) to U.S. Provisional Application No. 61/785,872, filed onMar. 14, 2013, which is incorporated herein by reference in itsentirety.

BACKGROUND

1. Field

The present invention relates to certain disubstituted 1,5-naphthyridineand quinoline compounds as inhibitors of monamine oxidase, and monoamineoxidase B in particular; derivatives of such compounds; compositions ofsuch compounds; methods of making them; and their use in variousmethods, including detection and imaging techniques; enhancing neuronalplasticity; treating neurological disorders, including neurodegenerativeand cognitive disorders; providing neuroprotection; enhancing theefficiency of cognitive and motor training; facilitating neurorecoveryand neurorehabilitation; and treating peripheral disorders, includingobesity, diabetes, cardiometabolic disorders, and their associatedco-morbidities.

2. Description of the Related Technology

Monoamine oxidase (MAO, E.C. 1.4.3.4) is a mitochondrial-bound,flavin-containing, enzyme that catalyzes the oxidative deamination ofbiogenic (endogenous) and xenobiotic (exogenous) amines. Biogenic aminescan be divided into three categories: monoamines, such as serotonin(5-hydroxytryptamine, 5-HT) and tryptamine; catecholamines, such asdopamine (DA), norepinephrine (NE), and epinephrine; and trace aminessuch as beta-phenylethylamine (PEA), tyramine, and octopamine.

Oxidative deamination by MAO requires the cofactor FAD and results information of the corresponding aldehyde, which then is usually rapidlyoxidized into a carboxylic acid by aldehyde dehydrogenase (ALDH). Thebyproducts of these reactions include potentially neurotoxic species,such as hydrogen peroxide and ammonia. Hydrogen peroxide, for example,can trigger the production of reactive oxygen species (ROS) and inducemitochondrial damage and neuronal apoptosis. Proper regulation of MAOstherefore appears crucial in maintaining proper nervous system function.

There are two MAO isoforms (types A and B), corresponding to the mao-Aand mao-B genes, and they show distinct expression patterns (e.g.,Riederer et al., J. Neural Transm. 1978, 43, 217-226; Saura et al., J.Neural Transm. Suppl. 1990, 32, 49-53; and Saura et al., Neuroscience1996, 70, 755-774). In peripheral tissues, MAO-A is primarily found inthe liver and gastrointestinal tract, whereas MAO-B is primarily foundin blood platelets. In the human brain, MAO-A is predominantly expressedin catecholaminergic neurons, whereas MAO-B is mostly concentrated inastrocytes and astroglia but also expressed in serotonergic neurons,histaminergic cells, and astrocytes. MAO-A and MAO-B also displayoverlapping but distinct substrate preferences: Both forms show asimilar preference for dopamine (DA), tyramine, and tryptamine; however,MAO-A preferentially metabolizes serotonin (5-HT) and noradrenaline(NE), whereas MAO-B preferentially metabolizes histamine andphenethylamine.

The ability of MAO enzymes to rapidly degrade brain monoamines such as5-HT, NE, and DA is essential for proper synaptic neurotransmission.Monoaminergic signaling is a key mechanism for modulating mood andemotion, as well as controlling motor, perceptual and cognitivefunctions. More generally, MAO-B levels in the brain naturally increasewith age, with significant increases observed after 50 to 60 years ofage. Increases in MAO-B contribute to cellular degeneration by producinghydrogen peroxides that are converted by iron to highly toxic oxygenfree radicals and leads to cell death. Likewise, perturbations in MAOactivity are associated with numerous pathological processes. Forexample, increased MAO-B activity in the brain has been observed inAlzheimer's and Parkinson's patients, implicating oxidative damage inneurodegenerative and cognitive dysfunction (e.g., Fowler et al., J.Neural. Transm, 1980, 49, 1-20; Dostert et al., Biochem. Pharmacol.1989, 38, 555-561; and Emilsson et al., Neurosci. Lett. 2002, 326,56-60).

These observations highlight the interest in MAO-inhibition as atherapeutic target for numerous disorders (e.g., Bentue-Ferrer et al.,CNS Drugs, 1996, 217-236). By increasing the concentration of monoaminespresent within the brain synapses, MAO inhibitors can enhancemonoamine-mediated neurotransmission, effectively treating neurologicaland psychiatric disorders such as Parkinson's disease and depression. Inaddition, because MAO inhibitors have demonstrated antioxidant andanti-apoptotic activity in experimental models, they may offerneuroprotective benefits by curbing the production of toxic oxidativespecies during MAO catalysis (e.g., Youdim et al., Nat. Rev. Neurosci.2006, 7, 295-309; Al-Nuaimi et al., Am. J. Ther. 2012, 19, 436-448.

A wide variety of MAO inhibitors been reported, includingphenylcoumarine derivatives (ES2343347, Jul. 28, 2010), substitutedazole derivatives (International Publication No. WO 2010098600, Sep. 2,2010), axabenzoxazole derivatives (WO 2010051196, May 6, 2010), pyrazolederivatives (US20070203154, Aug. 30, 2007), benzopyran derivatives (WO2006102958, Oct. 5, 2006), pyrrolidinylphenyl benzyl ether derivatives(WO 2006097270, Sep. 21, 2006), benzyloxybenzazepine derivatives (WO200503951, May 6, 2005), arylpyrrolidinone derivatives (WO 200402687,Apr. 1, 2004), and substituted oxadiazole derivatives (EP504574, Sep.23, 1992).

However, MAO inhibitors have generally been associated with numerousside effects that have typically limited their usefulness andtolerability. The first generation of MAO inhibitors—initiallyintroduced in the 1950s for treating depression—was irreversible andnon-selective. Use of these inhibitors was gradually abandoned mainlydue to their potential for drug-drug and drug-food interactions, themost widely known being with tyramine-containing food (the ‘cheese’effect). Moreover, when MAO inhibitors are used in high dosage,cardiovascular effects seem to increase considerably, and because MAOselectivity is lost with such high doses, tyramine can inducepotentially dangerous hypertensive reactions. More recent drugs,including selegiline and rasagiline, show greater selectivity for MAO-Band may have better side effect profiles, but they still suffer fromlimitations owing to irreversible binding (Chen and Swope, J. Clin.Pharmacol. 2005, 45, 878-894).

It is therefore desirable to develop improved MAO inhibitors such asthose showing higher potency, greater specificity, and better sideeffect profiles. The present invention meets these and other needs inthe art by disclosing substituted naphthyridine and quinoline compoundsas inhibitors of MAO, and more particularly, MAO-B.

SUMMARY

The invention provides a chemical entity of Formula (I):

whereinR¹, R², R³, Y, and n have any of the values described herein.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

Chemical entities of Formula (I) are useful in wide range of methods.Isotopically-labeled compounds and prodrugs can be used in metabolic andreaction kinetic studies, detection and imaging techniques, andradioactive treatments. The chemical embodiments of the presentinvention can be used to inhibit MAO, and MAO-B, in particular; to treata disorder mediated by MAO, and MAO-B, in particular; to enhanceneuronal plasticity; to treat neurological disorders, includingneurodegenerative disorders, cognitive disorders, and cognitive deficitsassociated with CNS disorders; to confer neuroprotection; and to treatperipheral disorders, including obesity, diabetes, cardiometabolicdisorders, and their associated co-morbidities. The chemical embodimentsof the present invention are also useful as augmenting agents to enhancethe efficiency of cognitive and motor training, to facilitateneurorecovery and neurorehabilitation, and to increase the efficiency ofnon-human animal training protocols. The invention is further directedto the general and specific embodiments defined, respectively, by theindependent and dependent claims appended hereto, which are incorporatedby reference herein.

DETAILED DESCRIPTION

The invention may be more fully appreciated by reference to thefollowing description, including the examples. Unless otherwise defined,all technical and scientific terms used herein have the same meaning ascommonly understood by one of ordinary skill in the art. Althoughmethods and materials similar or equivalent to those described hereincan be used in the practice or testing of the present invention,suitable methods and materials are described herein. In addition, thematerials, methods, and examples are illustrative only and not intendedto be limiting.

For the sake of brevity, all publications, including patentapplications, patents, and other citations mentioned herein, areincorporated by reference in their entirety. Citation of any suchpublication, however, shall not be construed as an admission that it isprior art to the present invention.

ABBREVIATIONS

The specification includes numerous abbreviations, whose meanings arelisted in the following Table:

Abbreviation Meaning ACN Acetonitrile BINAP2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl BOC tert-butoxycarbonyl BOCanhydride Di-tert-butyl dicarbonate DBU1,8-Diazabicyclo[5.4.0]undec-7-ene DCM Dichloromethane diglyme(2-Methoxyethyl) ether DIPEA N,N-ethyl-diisopropylamine orN,N-Diisopropyl- DMA N,N-Dimethylacetamide DMAP 4-Dimethylamino pyridineDME Dimethoxyethane DMF N,N-Dimethylformamide DMSO DimethylsulfoxideDowtherm ™ Biphenyl (C₁₂H₁₀) and Diphenyl oxide (C₁₂H₁₀O) eutecticmixture dppf 1,1′-Bis(diphenylphosphino)ferrocene EDCIN-(3-Dimethylaminopropyl)-N′- EtOAc, or EA Ethyl Acetate EtOH EthanolHATU 2-(1H-9-Azobenzotriazole-1-yl)-1,1,3,3- tetramethylaminiumhexafluorophosphate HOAc or AcOH Acetic Acid HOAT1-Hydroxy-7-azabenzotriazole HPLC High-performance liquid chromatographyKHMDS Potassium bis(trimethylsilyl)amide LAH Lithium aluminum hydrideLiHMDS, LHMDS Lithium bis(trimethylsilyl)amide LCMS, LC/MS Liquidchromatography-mass spectrometry MeOH Methanol MsCI Methanesulfonylchloride MTBE Methyl tert-butyl ether NMP 1-Methyl-2-pyrrolidinone Pd/CPalladium on activated carbon Pd₂(dba)₃Tris(dibenzylideneacetone)dipalladium (0) PdCl₂(dppf)-dcm [1′1′- adductBis(diphenylphosphino)ferrocene]palladium(ll) TEA, Et₃N TriethylamineTFA Trifluoroacetic acid THF Tetrahydrofuran TLC Thin layerchromatography XtalFluor ® (Diethylamino)difluorosulfoniumtetratetrafluoroborate

TERMS AND DEFINITIONS

The use of subheadings such as “General,” “Chemistry,” “Compositions,”“Formulations,” etc., in this section, as well as in other sections ofthis application, are solely for convenience of reference and notintended to be limiting.

General

As used herein, the term “about” or “approximately” means within anacceptable range for a particular value as determined by one skilled inthe art, and may depend in part on how the value is measured ordetermined, e.g., the limitations of the measurement system ortechnique. For example, “about” can mean a range of up to 20%, up to10%, up to 5%, or up to 1% or less on either side of a given value.Alternatively, with respect to biological systems or processes, the term“about” can mean within an order of magnitude, within 5 fold, or within2 fold on either side of a value. Numerical quantities given herein areapproximate unless stated otherwise, meaning that the term “about” or“approximately” can be inferred when not expressly stated

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that, whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation of such given valuethat would reasonably be inferred based on the ordinary skill in theart, including equivalents and approximations due to the experimentaland/or measurement conditions for such given value. Whenever a yield isgiven as a percentage, such yield refers to a mass of the entity forwhich the yield is given with respect to the maximum amount of the sameentity for which that could be obtained under the particularstoichiometric conditions. Concentrations that are given as percentagesrefer to mass ratios, unless indicated differently.

As used herein, the terms “a,” “an,” and “the” are to be understood asmeaning both singular and plural, unless explicitly stated otherwise.Thus, “a,” “an,” and “the” (and grammatical variations thereof whereappropriate) refer to one or more.

A group of items linked with the conjunction “and” should not be read asrequiring that each and every one of those items be present in thegrouping, but rather should be read as “and/or” unless expressly statedotherwise. Similarly, a group of items linked with the conjunction “or”should not be read as requiring mutual exclusivity among that group, butrather should also be read as “and/or” unless expressly statedotherwise. Furthermore, although items, elements or components of theinvention may be described or claimed in the singular, the plural iscontemplated to be within the scope thereof, unless limitation to thesingular is explicitly stated.

The terms “comprising” and “including” are used herein in their open,non-limiting sense. Other terms and phrases used in this document, andvariations thereof, unless otherwise expressly stated, should beconstrued as open ended, as opposed to limiting. As examples of theforegoing: the term “example” is used to provide exemplary instances ofthe item in discussion, not an exhaustive or limiting list thereof;adjectives such as “conventional,” “traditional,” “normal,” “criterion,”“known,” and terms of similar meaning should not be construed aslimiting the item described to a given time period or to an itemavailable as of a given time, but instead should be read to encompassconventional, traditional, normal, or criterion technologies that may beavailable or known now or at any time in the future. Likewise, wherethis document refers to technologies that would be apparent or known toone of ordinary skill in the art, such technologies encompass thoseapparent or known to the skilled artisan now or at any time in thefuture.

The presence of broadening words and phrases such as “one or more,” “atleast,” “but not limited to” or other like phrases in some instancesshall not be read to mean that the narrower case is intended or requiredin instances where such broadening phrases may be absent. As will becomeapparent to one of ordinary skill in the art after reading thisdocument, the illustrated embodiments and their various alternatives maybe implemented without confinement to the illustrated examples.

Chemistry

The term “alkyl” refers to a fully saturated aliphatic hydrocarbongroup. The alkyl moiety may be a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain. Examples of alkyl groupsinclude, but are not limited to, methyl (Me, which also may bestructurally depicted by the symbol, “

”), ethyl (Et), n-propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl (tBu), pentyl, isopentyl, tert-pentyl, hexyl, isohexyl, andgroups that in light of the ordinary skill in the art and the teachingsprovided herein would be considered equivalent to any one of theforegoing examples.

The term “haloalkyl” refers to a straight- or branched-chain alkyl grouphaving from 1 to 12 carbon atoms in the chain optionally substitutinghydrogens with halogens. Examples of haloalkyl groups include, but arenot limited to, —CF₃, —CHF₂, —CH₂F, —CH₂CF₃, —CH₂CHF₂, —CH₂CH₂F,—CH₂CH₂Cl, —CH₂CF₂CF₃. and other groups that in light of the ordinaryskill in the art and the teachings provided herein, would be consideredequivalent to any one of the foregoing examples.

The term “alkoxy” includes a straight chain or branched alkyl group withan oxygen atom linking the alkyl group to the rest of the molecule.Alkoxy includes methoxy, ethoxy, propoxy, isopropoxy, butoxy, t-butoxy,pentoxy and so on. “Aminoalkyl”, “thioalkyl”, and “sulfonylalkyl” areanalogous to alkoxy, replacing the terminal oxygen atom of alkoxy with,respectively, NH (or NR), S, and SO₂.

The term “cyano” refers to the group —CN.

The term “aryl” refers to a monocyclic, or fused or spiro polycyclic,aromatic carbocycle (ring structure having ring atoms that are allcarbon), having from 3 to 12 ring atoms per ring. (Carbon atoms in arylgroups are sp2 hybridized.) Illustrative examples of aryl groups includethe following moieties:

and the like.

The term “cycloalkyl” refers to a saturated or partially saturatedcarbocycle, such as monocyclic, fused polycyclic, bridged monocyclic,bridged polycyclic, spirocyclic, or spiro polycyclic carbocycle havingfrom 3 to 12 ring atoms per carbocycle. Where the term cycloalkyl isqualified by a specific characterization, such as monocyclic, fusedpolycyclic, bridged polycyclic, spirocyclic, and spiro polycyclic, thensuch term cycloalkyl refers only to the carbocycle so characterized.Illustrative examples of cycloalkyl groups include the followingentities, in the form of properly bonded moieties:

Those skilled in the art will recognize that the species of cycloalkylgroups listed or illustrated above are not exhaustive, and thatadditional species within the scope of these defined terms may also beselected.

The term “halogen” represents chlorine, fluorine, bromine or iodine. Theterm “halo” represents chloro, fluoro, bromo or iodo.

The term “heteroatom” used herein refers to, for example, O (oxygen), S(sulfur), or N (nitrogen).

The terms “para”, “meta”, and “ortho” have the meanings as understood inthe art. Thus, for example, a fully substituted phenyl group hassubstituents at both “ortho” (o) positions adjacent to the point ofattachment of the phenyl ring, both “meta” (m) positions, and the one“para” (p) position across from the point of attachment as illustratedbelow.

The term “substituted” means that the specified group or moiety bearsone or more substituents. The term “unsubstituted” means that thespecified group bears no substituents. The term “optionally substituted”means that the specified group is unsubstituted or substituted by one ormore substituents. Where the term “substituted” is used to describe astructural system, the substitution is meant to occur at anyvalency-allowed position on the system. In cases where a specifiedmoiety or group is not expressly noted as being optionally substitutedor substituted with any specified substituent, it is understood thatsuch a moiety or group is intended to be unsubstituted.

Formulas

Any formula given herein is intended to represent compounds havingstructures depicted by the structural formula as well as certainvariations or forms. In particular, compounds of any formula givenherein may have asymmetric centers and therefore exist in differentenantiomeric forms. All optical isomers and stereoisomers of thecompounds of the general formula, and mixtures thereof, are consideredwithin the scope of the formula. Thus, any formula given herein isintended to represent a racemate, one or more enantiomeric forms, one ormore diastereomeric forms, one or more atropisomeric forms, and mixturesthereof. Furthermore, certain structures may exist as geometric isomers(i.e., cis and trans isomers), as tautomers, or as atropisomers.

As used herein, “tautomer” refers to the migration of protons betweenadjacent single and double bonds. The tautomerization process isreversible. Compounds described herein can undergo any possibletautomerization that is within the physical characteristics of thecompound. The following is an example tautomerization that can occur incompounds described herein:

The symbols

and

are used as meaning the same spacial arrangement in chemical structuresshown herein. Analogously, the symbols

and

are used as meaning the same spatial arrangement in chemical structuresshown herein.

Compounds

As used herein, a “compound” refers to any one of: (a) the actuallyrecited form of such compound; and (b) any of the forms of such compoundin the medium in which the compound is being considered when named. Forexample, reference herein to a compound such as R—COOH, encompassesreference to any one of, for example, R—COOH(s), R—COOH(sol), andR—COO-(sol). In this example, R—COOH(s) refers to the solid compound, asit could be for example in a tablet or some other solid pharmaceuticalcomposition or preparation; R—COOH(sol) refers to the undissociated formof the compound in a solvent; and R—COO-(sol) refers to the dissociatedform of the compound in a solvent, such as the dissociated form of thecompound in an aqueous environment, whether such dissociated formderives from R—COOH, from a salt thereof, or from any other entity thatyields R—COO— upon dissociation in the medium being considered.

As used herein, the term “chemical entity” collectively refers to acompound, along with the derivatives of the compound, including salts,chelates, solvates, conformers, non-covalent complexes, metabolites, andprodrugs.

In one aspect the chemical entity is selected from the group consistingof compounds of Formula (I), pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically acceptable metabolites ofcompounds of Formula (I).

In another example, an expression such as “exposing an entity to acompound of formula R—COOH” refers to the exposure of such entity to theform, or forms, of the compound R—COOH that exists, or exist, in themedium in which such exposure takes place. In still another example, anexpression such as “reacting an entity with a compound of formulaR—COOH” refers to the reacting of (a) such entity in the chemicallyrelevant form, or forms, of such entity that exists, or exist, in themedium in which such reacting takes place, with (b) the chemicallyrelevant form, or forms, of the compound R—COOH that exists, or exist,in the medium in which such reacting takes place. In this regard, ifsuch entity is for example in an aqueous environment, it is understoodthat the compound R—COOH is in such same medium, and therefore theentity is being exposed to species such as R—COOH(aq) and/or R—COO-(aq),where the subscript “(aq)” stands for “aqueous” according to itsconventional meaning in chemistry and biochemistry. A carboxylic acidfunctional group has been chosen in these nomenclature examples; thischoice is not intended, however, as a limitation but it is merely anillustration. It is understood that analogous examples can be providedin terms of other functional groups, including but not limited tohydroxyl, basic nitrogen members, such as those in amines, and any othergroup that interacts or transforms according to known manners in themedium that contains the compound. Such interactions and transformationsinclude, but are not limited to, dissociation, association, tautomerism,solvolysis, including hydrolysis, solvation, including hydration,protonation and deprotonation. No further examples in this regard areprovided herein because these interactions and transformations in agiven medium are known by any one of ordinary skill in the art.

In another example, a “zwitterionic” compound is encompassed herein byreferring to a compound that is known to form a zwitterion, even if itis not explicitly named in its zwitterionic form. Terms such aszwitterion, zwitterions, and their synonyms zwitterionic compound(s) arestandard IUPAC-endorsed names that are well known and part of standardsets of defined scientific names. In this regard, the name zwitterion isassigned the name identification CHEBI:27369 by the Chemical Entities ofBiological Interest (ChEBI) dictionary of molecular entities. As isgenerally well known, a zwitterion or zwitterionic compound is a neutralcompound that has formal unit charges of opposite sign. Sometimes thesecompounds are referred to by the term “inner salts”. Other sources referto these compounds as “dipolar ions”, although the latter term isregarded by still other sources as a misnomer. As a specific example,aminoethanoic acid (the amino acid glycine) has the formula H₂NCH₂COOH,and it exists in some media (in this case in neutral media) in the formof the zwitterion +H₃NCH₂COO—. Zwitterions, zwitterionic compounds,inner salts, and dipolar ions in the known and well established meaningsof these terms are within the scope of this invention, as would in anycase be so appreciated by those of ordinary skill in the art. Becausethere is no need to name each and every embodiment that would berecognized by those of ordinary skill in the art, no structures of thezwitterionic compounds that are associated with the compounds of thisinvention are given explicitly herein. They are, however, part of theembodiments of this invention. No further examples in this regard areprovided herein because the interactions and transformations in a givenmedium that lead to the various forms of a given compound are known byany one of ordinary skill in the art.

Isotopes may be present in the compounds described. Each chemicalelement present in a compound either specifically or genericallydescribed herein may include any isotope of said element. Any formulagiven herein is also intended to represent isotopically labeled forms ofthe compounds. Isotopically labeled compounds have structures depictedby the formulas given herein except that one or more atoms are replacedby an atom having a selected atomic mass or mass number. Examples ofisotopes that can be incorporated into compounds of the inventioninclude isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus,sulfur, fluorine, chlorine, and iodine, such as ²H, ³H, ¹¹C, ¹³C, ¹⁴C,¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F, ³⁶Cl, and ¹²⁵I.

When referring to any formula given herein, the selection of aparticular moiety from a list of possible species for a specifiedvariable is not intended to define the same choice of the species forthe variable appearing elsewhere. In other words, where a variableappears more than once, the choice of the species from a specified listis independent of the choice of species for the same variable elsewherein the formula, unless otherwise stated.

By way of a first example on substituent terminology, if substituent S¹_(example) is one of S₁ and S₂, and substituent S² _(example) is one ofS₃ and S₄, then these assignments refer to embodiments of this inventiongiven according to the choices S¹ _(example) is S₁ and S² _(example) isS₃; S¹ _(example) is S₁ and S² _(example) is S₄; S¹ _(example) is S₂ andS² _(example) is S₃; S¹ _(example) is S₂ and S² _(example) is S₄; andequivalents of each one of such choices. The shorter terminology “S¹_(example) is one of S₁ and S₂ and “S² _(example) is one of S₃ and S₄ isaccordingly used herein for the sake of brevity but not by way oflimitation. The foregoing first example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R^(a), R^(b), R^(c), R^(d), R^(e) and Y and any other genericsubstituent symbol used herein.

Furthermore, when more than one assignment is given for any member orsubstituent, embodiments of this invention comprise the variousgroupings that can be made from the listed assignments, takenindependently, and equivalents thereof. By way of a second example onsubstituent terminology, if it is herein described that substituentS_(example) is one of S₁, S₂ and S₃, the listing refers to embodimentsof this invention for which S_(example) is S₁; S_(example) is S₂;S_(example) is S₃; S_(example) is one of S₁ and S₂; S_(example) is oneof S₁ and S₃; S_(example) is one of S₂ and S₃; S_(example) is one of S₁,S₂ and S₃; and S_(example) is any equivalent of each one of thesechoices. The shorter terminology “S_(example) is one of S₁, S₂ and S₃”is accordingly used herein for the sake of brevity, but not by way oflimitation. The foregoing second example on substituent terminology,which is stated in generic terms, is meant to illustrate the varioussubstituent assignments described herein. The foregoing convention givenherein for substituents extends, when applicable, to members such as R¹,R², R^(a), R^(b), R^(c), R^(d), R^(e) and Y and any other genericsubstituent symbol used herein.

The nomenclature “C_(i-j)” with j>i, when applied herein to a class ofsubstituents, is meant to refer to embodiments of this invention forwhich each and every one of the number of carbon members, from i to jincluding i and j, is independently realized. By way of example, theterm C₁₋₃ refers independently to embodiments that have one carbonmember (C₁), embodiments that have two carbon members (C₂), andembodiments that have three carbon members (C₃).

The term C_(n-m)alkyl refers to an aliphatic chain, whether straight orbranched, with the total number N of carbon members in the chain thatsatisfies n≦N≦m, with m>n.

Any disubstituent referred to herein is meant to encompass the variousattachment possibilities when more than one of such possibilities areallowed. For example, reference to disubstituent -A-B—, where A≠B,refers herein to such disubstituent with A attached to a firstsubstituted member and B attached to a second substituted member, and italso refers to such disubstituent with A attached to the second memberand B attached to the first substituted member.

According to the foregoing interpretive considerations on assignmentsand nomenclature, it is understood that explicit reference herein to aset implies, where chemically meaningful and unless indicated otherwise,independent reference to embodiments of such set, and reference to eachand every one of the possible embodiments of subsets of the set referredto explicitly.

The term “prodrug” means a precursor of a designated compound that,following administration to a subject, yields the compound in vivo via achemical or physiological process such as solvolysis or enzymaticcleavage, or under physiological conditions (e.g., a prodrug on beingbrought to physiological pH is converted to the compound of Formula(I)).

A “pharmaceutically acceptable prodrug” is a prodrug that is preferablynon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to the subject. Illustrative procedures for theselection and preparation of suitable prodrug derivatives are described,for example, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

A “metabolite” means a pharmacologically active product of metabolism inthe body of a compound of Formula (I) or salt thereof. Preferably, themetabolite is in an isolated form outside the body.

Compositions

The term “composition,” as in pharmaceutical composition, is intended toencompass a product comprising the active ingredient(s), and the inertingredient(s) (pharmaceutically acceptable excipients) that make up thecarrier, as well as any product which results, directly or indirectly,from combination, complexation, or aggregation of any two or more of theingredients, or from dissociation of one or more of the ingredients, orfrom other types of reactions or interactions of one or more of theingredients. Accordingly, the pharmaceutical compositions of the presentinvention encompass any composition made by admixing a compound ofFormula (I) and a pharmaceutically acceptable excipient.

The term “pharmaceutically acceptable,” as used in connection withcompositions of the invention, refers to molecular entities and otheringredients of such compositions that are physiologically tolerable anddo not typically produce untoward reactions when administered to ananimal (e.g., human). The term “pharmaceutically acceptable” may alsomean approved by a regulatory agency of the Federal or a stategovernment or listed in the U.S. Pharmacopeia or other generallyrecognized pharmacopeia for use in animals (e.g. mammals), and moreparticularly in humans.

A “pharmaceutically acceptable excipient” refers to a substance that isnon-toxic, biologically tolerable, and otherwise biologically suitablefor administration to a subject, such as an inert substance, added to apharmacological composition or otherwise used as a vehicle, carrier, ordiluents to facilitate administration of an agent and that is compatibletherewith. Examples of excipients include calcium carbonate, calciumphosphate, various sugars and types of starch, cellulose derivatives,gelatin, vegetable oils, and polyethylene glycols. Suitablepharmaceutical carriers include those described in Remington: TheScience and Practice of Pharmacy, 21^(st) Ed., Lippincott Williams &Wilkins (2005).

A “pharmaceutically acceptable salt” is intended to mean a salt of afree acid or base of a compound represented by Formula (I) that isnon-toxic, biologically tolerable, or otherwise biologically suitablefor administration to the subject. See, generally, G. S. Paulekuhn etal., Trends in Active Pharmaceutical Ingredient Salt Selection based onAnalysis of the Orange Book Database, J. Med. Chem. 2007, 50, 6665-6672;Berge et al., Pharmaceutical Salts, J. Pharm. Sci. 1977, 66, 1-19; Stahland Wermuth (eds), Pharmaceutical Salts; Properties, Selection, and Use:2nd Revised Edition, Wiley-VCS, Zurich, Switzerland (2011). Examples ofpharmaceutically acceptable salts are those that are pharmacologicallyeffective and suitable for contact with the tissues of patients withoutundue toxicity, irritation, or allergic response. A compound of Formula(I) may possess a sufficiently acidic group, a sufficiently basic group,or both types of functional groups, and accordingly react with a numberof inorganic or organic bases, and inorganic and organic acids, to forma pharmaceutically acceptable salt bases, and inorganic and organicacids, to form a pharmaceutically acceptable salt.

The term “carrier” refers to an adjuvant, vehicle, or excipients, withwhich the compound is administered. In preferred embodiments of thisinvention, the carrier is a solid carrier. Suitable pharmaceuticalcarriers include those described in Remington: The Science and Practiceof Pharmacy, 21^(st) Ed., Lippincott Williams & Wilkins (2005).

The term “dosage form,” as used herein, is the form in which the dose isto be administered to the subject or patient. The drug is generallyadministered as part of a formulation that includes nonmedical agents.The dosage form has unique physical and pharmaceutical characteristics.Dosage forms, for example, may be solid, liquid or gaseous. “Dosageforms” may include, for example, a capsule, tablet, caplet, gel caplet(gelcap), syrup, a liquid composition, a powder, a concentrated powder,a concentrated powder admixed with a liquid, a chewable form, aswallowable form, a dissolvable form, an effervescent, a granulatedform, and an oral liquid solution. In a specific embodiment, the dosageform is a solid dosage form, and more specifically, comprises a tabletor capsule.

As used herein, the term “inert” refer to any inactive ingredient of adescribed composition. The definition of “inactive ingredient” as usedherein follows that of the U.S. Food and Drug Administration, as definedin 21 C.F.R. 201.3(b)(8), which is any component of a drug product otherthan the active ingredient.

Methods and Uses

As used herein, the term “disorder” is used interchangeably with“disease” or “condition”. For example, a CNS disorder also means a CNSdisease or a CNS condition.

As used herein, the term “cognitive impairment” is used interchangeablywith “cognitive dysfunction” or “cognitive deficit,” all of which aredeemed to cover the same therapeutic indications.

The terms “treating,” “treatment,” and “treat” cover therapeutic methodsdirected to a disease-state in a subject and include: (i) preventing thedisease-state from occurring, in particular, when the subject ispredisposed to the disease-state but has not yet been diagnosed ashaving it; (ii) inhibiting the disease-state, e.g., arresting itsdevelopment (progression) or delaying its onset; and (iii) relieving thedisease-state, e.g., causing regression of the disease state until adesired endpoint is reached. Treating also includes ameliorating asymptom of a disease (e.g., reducing the pain, discomfort, or deficit),wherein such amelioration may be directly affecting the disease (e.g.,affecting the disease's cause, transmission, or expression) or notdirectly affecting the disease.

As used in the present disclosure, the term “effective amount” isinterchangeable with “therapeutically effective amount” and means anamount or dose of a compound or composition effective in treating theparticular disease, condition, or disorder disclosed herein, and thus“treating” includes producing a desired preventative, inhibitory,relieving, or ameliorative effect. In methods of treatment according tothe invention, “an effective amount” of at least one compound accordingto the invention is administered to a subject (e.g., a mammal). An“effective amount” also means an amount or dose of a compound orcomposition effective to modulate activity of MAO-B or an associatedsignaling pathway, such as the CREB pathway and thus produce the desiredmodulatory effect. The “effective amount” will vary, depending on thecompound, the disease, the type of treatment desired, and its severity,and age, weight, etc.

The term “animal” is interchangeable with “subject” and may be avertebrate, in particular, a mammal, and more particularly, a human, andincludes a laboratory animal in the context of a clinical trial orscreening or activity experiment. Thus, as can be readily understood byone of ordinary skill in the art, the compositions and methods of thepresent invention are particularly suited to administration to anyvertebrate, particularly a mammal, and more particularly, a human.

As used herein, a “control animal” or a “normal animal” is an animalthat is of the same species as, and otherwise comparable to (e.g.,similar age, sex), the animal that is trained under conditionssufficient to induce transcription-dependent memory formation in thatanimal.

By “enhance,” “enhancing” or “enhancement” is meant the ability topotentiate, increase, improve or make greater or better, relative tonormal, a biochemical or physiological action or effect. For example,enhancing long term memory formation refers to the ability to potentiateor increase long term memory formation in an animal relative to thenormal long term memory formation of the animal or controls. As aresult, long term memory acquisition is faster or better retained.Enhancing performance of a cognitive task refers to the ability topotentiate or improve performance of a specified cognitive task by ananimal relative to the normal performance of the cognitive task by theanimal or controls.

As used herein, the term “training protocol,” or “training,” refers toeither “cognitive training” or “motor training.” The phrase “inconjunction” means that a compound or composition of the presentinvention enhances CREB pathway function during cognitive or motortraining.

Reference will now be made to the embodiments of the present invention,examples of which are illustrated by and described in conjunction withthe accompanying drawings and examples. While certain embodiments aredescribed herein, it is understood that the described embodiments arenot intended to limit the scope of the invention. On the contrary, thepresent disclosure is intended to cover alternatives, modifications, andequivalents that can be included within the invention as defined by theappended claims.

Compounds

The present invention provides disubstituted 1,5-naphthyridine andquinoline compounds, which are useful as inhibitors or monoamineoxidase, and monoamine oxidase B specifically. They are distinct fromthiazolidine substituted quinoline compounds, which have been reportedfor treating diabetes (International Publication No. WO2003057216, Jul.17, 2003), lowering visceral fat (International Publication No.WO9820871, May 22, 1998), and reducing blood sugar levels (InternationalPublication No. WO9612710, May 2, 1996). They are also distinct fromsubstituted quinoline compounds reported for treating diabetes(JP2002322163, Nov. 8, 2002; International Publication No. WO9828254,Jul. 2, 1998).

In its many embodiments, the invention is directed to a chemical entityof Formula

whereinR¹, R², R³, Y, and n have any of the values described herein.

In its many embodiments, the invention is directed to a chemical entityof Formula (I):

n is 0, 1, 2, or 3;

Y is CH or N;

R¹ is a pyridine substituted with C₁₋₆haloalkyl or an aryl substitutedwith one, two, or three R^(a) members;

-   -   each R^(a) is independently selected from the group consisting        of halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —NO₂, and —OC₁₋₆alkyl;

R² is selected from the group consisting of —C(R^(b))₂R^(c) or—CO—R^(d);

-   -   each R^(b) is selected from the group consisting of —H, —F, and        —C₁₋₆alkyl, or optionally two R^(b) members are taken together        with the carbon to which they are attached to form a        C₃₋₈cycloalkyl ring;    -   R^(c) is selected from the group consisting of -halo, —NH₂, —OH,        —OC₁₋₆alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and        —C(CH₃)₂OH; provided that when at least one R^(b) is —F then        R^(c) is not —F;    -   R^(d) is selected from the group consisting of -alkyl,        —OC₁₋₆alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂;    -   each R^(e) is independently —H and —C₁₋₆alkyl; and

R³ is selected from the group consisting of —H, —C₁₋₆alkyl, —OH,—OC₁₋₆alkyl, and C₁₋₆haloalkyl.

In a specific aspect, a compound, or a pharmaceutically acceptable saltthereof, of Formula (I) corresponding to the first embodiment mayinclude one or more the following: n is 1, 2 or 3; Y is CH or N; R¹ is apyridine substituted with C₁₋₄haloalkyl or an aryl substituted with 1,2, or 3 R^(a) members; each R^(a) is independently selected from thegroup consisting of halo, —C₁₋₄alkyl, —C₁₋₄haloalkyl, —NO₂, and—OC₁₋₄alkyl; R² is —C(R^(b))₂R^(c) or —CO—R^(d); each R^(b) isindependently selected from the group consisting of —H, —F, and—C₁₋₄alkyl, or optionally two R^(b) members are taken together with thecarbon to which they are attached to form a C₃₋₈cycloalkyl ring; R^(c)is selected from the group consisting of -halo, —NH₂, —OH, —OC₁₋₄alkyl,—CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and —C(CH₃)₂OH; provided thatwhen at least one R^(b) is —F then R^(c) is not —F; R^(d) is selectedfrom the group consisting of -alkyl, —OC₁₋₄alkyl, —NHR^(e), and—NHCH₂CH₂N(R^(e))₂; each R^(e) is independently —H or —C₁₋₄alkyl; and R³is selected from the group consisting of —H, —C₁₋₄alkyl, —OH,—OC₁₋₄alkyl, and C₁-C₄haloalkyl.

In a second embodiment of a compound, or a pharmaceutically acceptablesalt thereof, of Formula (I),

n is 0, 1, or 2;

Y is CH or N;

R¹ is a pyridine substituted with —CF₃, or a phenyl substituted in themeta or para positions with one, two, or three R^(a) members;

-   -   each R^(a) is independently selected from the group consisting        of halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, —NO₂, and —OC₁₋₄alkyl;

R² is selected from the group consisting of —C(R^(b))₂R^(c) or—CO—R^(d);

-   -   each R^(b) is independently selected from the group consisting        of —H, —F, and —C₁₋₆alkyl, or optionally two R^(b) members are        taken together with the carbon to which they are attached to        form a C₃₋₈cycloalkyl ring;    -   R^(c) is selected from the group consisting of —F, —NH₂, —OH,        —OC₁₋₃alkyl, —CH₂OH, —CN, —CO₂—C₁₋₆alkyl, —CO—NHR^(e), and        —C(CH₃)₂OH; provided that when at least one R^(b) is —F then        R^(c) is not —F;    -   R^(d) is selected from the group consisting of —CH₃,        —OC₁₋₄alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂;    -   each R^(e) is independently —H or —CH₃; and    -   R³ is selected from the group consisting of —H, —CH₃, —OH, and        —CF₃.

In a specific aspect, a compound, or a pharmaceutically acceptable saltthereof, of Formula 1 corresponding to the second embodiment may includeone or more the following: n=1 or 2; Y is CH or N; R¹ is a pyridinesubstituted with —CF₃, or a phenyl substituted in the meta or parapositions with one, two, or three R^(a) members; R^(a) is independentlyselected from the group consisting of halo, —C₁₋₄alkyl, CF₃, —NO₂, and—OC₁₋₄alkyl; R² is selected from the group consisting of —C(R^(b))₂R^(c)or —CO—R^(d); each R^(b) is independently selected from the groupconsisting of —H, —F, and —C₁₋₃alkyl, or optionally two R^(b) membersare taken together with the carbon to which they are attached to form aC₃₋₆cycloalkyl ring; R^(c) is selected from the group consisting of: —F,—NH₂, —OH, —OC₁₋₃alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and—C(CH₃)₂OH; provided that when at least one R^(b) is —F then R^(c) isnot —F; R^(d) is selected from the group consisting of —CH₃,—OC₁₋₄alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂; each R^(e) isindependently —H or —CH₃; and R³ is a member selected from the groupconsisting of —H, —CH₃, —OH, and —CF₃.

In a third embodiment of a compound, or a pharmaceutically acceptablesalt thereof, of Formula (I), n is 1 or 2;

Y is CH or N;

R¹ is a pyridine substituted with —CF₃, or a phenyl substituted in themeta or para positions with one, two, or three R^(a) members;

-   -   each R^(a) is independently selected from the group consisting        of halo, —C₁₋₆alkyl, —C₁₋₆haloalkyl, OC₁₋₆alkyl CF₃, —NO₂, and;

R² is selected from the group consisting of —C(R^(b))₂R^(c) or—CO—R^(d);

-   -   each R^(b) is independently selected from the group consisting        of —H, —F, —C₁₋₆alkyl, or optionally two R^(b) members are taken        together with the carbon to which they are attached to form a        C₃₋₈cycloalkyl ring;    -   R^(c) is selected from the group consisting of: —F, —NH₂, —OH,        —OC₁₋₃alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and        —C(CH₃)₂OH; provided that provided that when at least one R^(b)        is —F then R^(c) is not —F;    -   R^(d) is selected from the group consisting of: —CH₃,        —OC₁₋₆alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂;    -   each R^(e) is independently selected from the group consisting        of —H and —CH₃; and    -   R³ is selected from the group consisting of —H, —CH₃, —OH, and        —CF₃.

In a specific aspect, a compound, or a pharmaceutically acceptable saltthereof, of Formula 1 corresponding to the third embodiment may includeone or more the following: n is 1 or 2; R² is selected from the groupconsisting of —C(R^(b))₂R^(c) or —CO—R^(d); R^(b) is selected from thegroup consisting of —H, —F, —C₁₋₄alkyl, or optionally two R^(b) membersare taken together with the carbon to which they are attached to form aC₃₋₆cycloalkyl ring; R^(c) is selected from the group consisting of:-halo, —NH₂, —OH, —OC₁₋₄alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e),and —C(CH₃)₂OH; provided that when at least one R^(b) is —F then R^(c)is not —F; R^(d) is selected from the group consisting of: -alkyl,—OC₁₋₄alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂; each R^(e) isindependently selected from the group consisting of —H and —C₁₋₄alkyl;and R³ is selected from the group consisting of —H, —C₁₋₄alkyl, —OH,—OC₁₋₄alkyl, and C₁-C₄haloalkyl.

In certain embodiments, n is 1.

In certain embodiments, n is 2.

In certain embodiments, Y is CH.

In certain embodiments, Y is N.

In some embodiments, R¹ is 2-(trifluoromethyl)pyridin-4-yl or6-(trifluoromethyl)pyridin-2-yl.

In some embodiments, R¹ is phenyl substituted with R^(a), and R^(a) ishalo, C₁₋₄alkyl, —C₁₋₄haloalkyl, —OC₁₋₄alkyl, or —NO₂.

In some embodiments, R¹ is 3-chlorophenyl, 3-fluorophenyl,3-nitrophenyl, 3-methylphenyl, 3-methoxyphenyl,3-(trifluoromethyl)phenyl, 3-chloro-4-fluorophenyl, 3,4-difluorophenyl,3-chloro-5-fluorophenyl, 3,5-difluorophenyl,3-fluoro-5-(trifluoromethyl)phenyl, 3,4,5-trifluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-(trifluoromethyl)phenyl,4-fluoro-3-(trifluoromethyl)phenyl, 4-nitrophenyl, 4-methoxyphenyl,2-(trifluoromethyl)pyridin-4-yl, or 6-(trifluoromethyl)pyridin-2-yl.

In some embodiments, R² is —(CR^(b))₂R^(c), and n is 1.

In some embodiments, R^(b) is —H, halo or —CH₃.

In some embodiments, two R^(b) groups are taken together with the carbonto which they are attached to form a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl ring.

In some embodiments, R^(c) is halo, —NH₂, —OH, —OCH₃, —CH₂OH, —CN,—CO₂—C₁₋₄alkyl, —CO—NHR^(e), and —C(CH₃)₂OH.

In some embodiments, R² is —CH₂NH₂, —CH₂OH, —CH₂CH₂OH, —CH₂OCH₃, —CH₂CN,—CH₂(C═O)OCH₃, —CH₂(C═O)OCH₂CH₃, —CH₂(C═O)NH₂, —CH₂(CH₃)₂OH, —CH(OH)CH₃,—C(CH₃)₂OH, —C(CH₃)₂CH₂OH, —C(CH₃)₂(C═O)NH₂, —OCH₂CH₃, or —CF(CH₃)₂.

In some embodiments, R² is —CO—R^(d), and n is 1.

In some embodiments, R^(d) is —CH₃, —OC₁₋₄alkyl, —NH₂, —NH(CH₃),—NHCH₂CH₂NH(CH₃) or —NHCH₂CH₂N(CH₃)₂

In some embodiments, R² is —(C═O)CH₃, —C(═O)OCH₃, —C(═O)OCH₂CH₃,—(C═O)NH₂, —(C═O)NHCH₃, —(C═O)N(CH₃)₂, —(C═O)NHCH₂CH₂NH₂,—(C═O)NHCH₂CH₂NHCH₃, or —(C═O)NHCH₂CH₂N(CH₃)₂.

In certain embodiments, R³ is H or —CH₃.

In certain embodiments, R³ is —CF₃ or —OH.

In certain embodiments, R¹ is

each R^(1a) is independently selected from the group consisting of —H,halo, —C₁₋₄alkyl, CF₃, —NO₂, and —OC₁₋₄alkyl; R^(1b) is selected fromthe group consisting of halo, —C₁₋₄alkyl, CF₃, —NO₂, and —OC₁₋₄alkyl;R^(1c) is selected from the group consisting of halo, —C₁₋₄alkyl, CF₃,—NO₂, and —OC₁₋₄alkyl; R^(1d) is selected from the group consisting of—H, halo, —C₁₋₄alkyl, CF₃, —NO₂, and —OC₁₋₄alkyl; and R^(1e) is selectedfrom the group consisting of —H, halo, —C₁₋₄alkyl, CF₃, —NO₂, and—OC₁₋₄alkyl.

Further embodiments are provided by pharmaceutically acceptable salts ofcompounds of Formula (I), pharmaceutically acceptable prodrugs ofcompounds of Formula (I), and pharmaceutically active metabolites ofcompounds of Formula (I).

In certain embodiments, a compound, or a pharmaceutically acceptablesalt thereof, of Formula (I), is selected from the group consisting of:

Example # Compound Name 1 Ethyl7-[(4-chlorophenyl)methoxy]quinoline-3-carboxylate; 2 Ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate; 3 Ethyl7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate; 4 Ethyl7-[(3-fluorophenyl)methoxy]quinoline-3-carboxylate; 5 Ethyl7-((3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; 6 Ethyl7-((4-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; 7 Ethyl7-((3-methylbenzyl)oxy)quinoline-3-carboxylate; 8 Ethyl7-((4-methylbenzyl)oxy)quinoline-3-carboxylate; 9 Ethyl7-((3-methoxybenzyl)oxy)quinoline-3-carboxylate; 10 Ethyl7-((4-methoxybenzyl)oxy)quinoline-3-carboxylate; 11 Ethyl7-((4-nitrobenzyl)oxy)quinoline-3-carboxylate; 12 Ethyl7-((4-fluoro-3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; 13Ethyl7-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; 14Ethyl 7-((3,4-difluorobenzyl)oxy)quinoline-3-carboxylate; 15 Ethyl7-((3,5-difluorobenzyl)oxy)quinoline-3-carboxylate; 16 Ethyl7-((3,4,5-trifluorobenzyl)oxy)quinoline-3-carboxylate; 17 Ethyl7-((3-chloro-4-fluorobenzyl)oxy)quinoline-3-carboxylate; 18 Ethyl7-((3-nitrobenzyl)oxy)quinoline-3-carboxylate; 19 Ethyl7-((3-chloro-5-fluorobenzyl)oxy)quinoline-3-carboxylate; 20 Ethyl7-((3-chlorobenzyl)oxy)-2-methylquinoline-3-carboxylate; 21 Ethyl7-((3-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; 22 Ethyl7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; 23 Ethyl7-((3-chloro-4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; 24Ethyl 7-(3-fluorophenethoxy)quinoline-3-carboxylate; 25 Ethyl7-(3-chlorophenethoxy)quinoline-3-carboxylate; 26 Methyl7-((3-chlorobenzyl)oxy)quinoline-3-carboxylate; 272-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol; 282-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)propan-2-ol; 292-(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)propan-2-ol; 302-(7-((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)propan-2-ol; 312-(7-((4-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol; 322-(7-((3-Chlorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol; 332-(7-((3-Chloro-4-fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;34 2-(7-((3-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol; 35(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanol; 36(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)methanol; 37(7-((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)methanol; 382-(7-(3-Fluorophenethoxy)quinolin-3-yl)propan-2-ol; 392-(7-(3-Chlorophenethoxy)quinolin-3-yl)propan-2-ol; 407-((3-Chlorobenzyl)oxy)-3-(methoxymethyl)quinoline; 417-((4-Fluorobenzyl)oxy)-3-(2-fluoropropan-2-yl)quinoline; 421-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanone; 431-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol; 44(R)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol; 45(S)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol; 467-((3-Chlorobenzyl)oxy)-N-methylquinoline-3-carboxamide; 47N-(2-Aminoethyl)-7-((3-chlorobenzyl)oxy)quinoline-3-carboxamide; 487-((3-Chlorobenzyl)oxy)-N-(2-(methylamino)ethyl)quinoline-3-carboxamide;49 7-((3-Chlorobenzyl)oxy)-N-(2-(dimethylamino)ethyl)quinoline-3-carboxamide; 50 (7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanamine; 512-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide; 52 Ethyl2-(7-((3-fluorobenzyl)oxy)quinolin-3-yl)acetate; 53 Ethyl2-(7-((4-fhiorobenzyl)oxy)quinolin-3-yl)acetate; 54 Methyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate; 552-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide; 562-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)ethanol; 572-(7-((3-Fluorobenzyl)oxy)quinolin-3-yl)acetamide; 582-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)acetamide; 59 Ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate; 602-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-1-ol; 612-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanamide; 622-(7-((2-(Trifluoromethyl)pyridin-4-yl)methoxy)quinolin-3-yl)acetamide;63 1-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-2-ol; 647-((3-Chlorobenzyl)oxy)quinoline-3-carboxamide; 652-{7-[(4-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol; 667-[(4-Fluorophenyl)methoxy]-3-(2-hydroxypropan-2-yl)quinolin-1-ium-1-olate; 67 7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide;68 7-((4-Fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide; 697-((3-Chlorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide; 707-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide; 717-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide; 727-[(3-Chlorophenyl)methoxy]-N-methyl-1,5-naphthyridine-3-carboxamide; 73(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol; 742-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}acetonitrile;753-[(4-Fluorophenyl)methoxy]-7-(2-fluoropropan-2-yl)-1,5-naphthyridine;76 2-{7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol; 772-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol; 782-{7-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;79 2-{7-[(3-Chlorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol; 802-(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamide; 812-(7-((6-(Trifluoromethyl)pyridin-2-yl)methoxy)-1,5-naphthyridin-3yl)acetamide; 822-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide;and 832-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetamide.Isotopically-Labeled Compounds

The invention also includes isotopically-labeled compounds, which areidentical to those recited in Formula I, but for the fact that one ormore atoms are replaced by an atom having an atomic mass or mass numberdifferent from the atomic mass or mass number usually found in nature.Examples of isotopes that can be incorporated into compounds of theinvention include isotopes of carbon, chlorine, fluorine, hydrogen,iodine, nitrogen, oxygen, phosphorous, sulfur, and technetium, including¹¹C, ¹³C, ¹⁴C, ³⁶Cl, ¹⁸F, ²H, ³H, ¹²³I, ¹²⁵I, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O,³¹P, ³²P, ³⁵S, and ^(99m)Tc.

Compounds of the present invention (and derivatives of such compounds,such as pharmaceutically acceptable salts and prodrugs) that contain theaforementioned isotopes or other isotopes of other atoms are within thescope of the invention. Isotopically-labeled compounds of the presentinvention are useful in drug and substrate tissue distribution andtarget occupancy assays. For example, isotopically labeled compounds areparticularly useful in SPECT (single photon emission computedtomography) and in PET (positron emission tomography), as discussedfurther herein.

Derivatives

The present invention also provides derivatives of a chemical entity ofFormula (I), which include, but are not limited to, a salt, solvate,conformer, or crystalline form/polymorph.

Salts

Accordingly, in one embodiment the invention includes pharmaceuticallyacceptable salts of the compounds represented by Formula (I), andmethods using such salts.

Examples of pharmaceutically acceptable salts include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, phosphates,monohydrogen-phosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates, borate, nitrate,propionates, decanoates, caprylates, acrylates, formates, isobutyrates,caproates, heptanoates, propiolates, oxalates, malonates, succinates,suberates, sebacates, fumarates, maleates, butyne-1,4-dioates,hexyne-1,6-dioates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, hydroxybenzoates, methoxybenzoates, phthalates,sulfonates, xylenesulfonates, phenylacetates, phenylpropionates,phenylbutyrates, citrates, lactates, y-hydroxybutyrates, glycolates,tartrates, methane-sulfonates, propanesulfonates,naphthalene-1-sulfonates, naphthalene-2-sulfonates, besylate, mesylateand mandelates.

When the compound of Formula (I) contains a basic nitrogen, the desiredpharmaceutically acceptable salt may be prepared by any suitable methodavailable in the art, for example, treatment of the free base with aninorganic acid, such as hydrochloric acid, hydrobromic acid, sulfuricacid, sulfamic acid, nitric acid, boric acid, phosphoric acid, and thelike, or with an organic acid, such as acetic acid, phenylacetic acid,propionic acid, stearic acid, lactic acid, ascorbic acid, maleic acid,hydroxymaleic acid, isethionic acid, succinic acid, valeric acid,fumaric acid, malonic acid, pyruvic acid, oxalic acid, glycolic acid,salicylic acid, oleic acid, palmitic acid, lauric acid, a pyranosidylacid, such as glucuronic acid or galacturonic acid, an alpha-hydroxyacid, such as mandelic acid, citric acid, or tartaric acid, an aminoacid, such as aspartic acid, glutaric acid or glutamic acid, an aromaticacid, such as benzoic acid, 2-acetoxybenzoic acid, naphthoic acid, orcinnamic acid, a sulfonic acid, such as laurylsulfonic acid,p-toluenesulfonic acid, methanesulfonic acid, ethanesulfonic acid, anycompatible mixture of acids such as those given as examples herein, andany other acid and mixture thereof that are regarded as equivalents oracceptable substitutes in light of the ordinary level of skill in thistechnology.

When the compound of Formula (I) is an acid, such as a carboxylic acidor sulfonic acid, the desired pharmaceutically acceptable salt may beprepared by any suitable method, for example, treatment of the free acidwith an inorganic or organic base, such as an amine (primary, secondaryor tertiary), an alkali metal hydroxide, alkaline earth metal hydroxide,any compatible mixture of bases such as those given as examples herein,and any other base and mixture thereof that are regarded as equivalentsor acceptable substitutes in light of the ordinary level of skill inthis technology. Illustrative examples of suitable salts include organicsalts derived from amino acids, such as N-methyl-O-glucamine, lysine,choline, glycine and arginine, ammonia, carbonates, bicarbonates,primary, secondary, and tertiary amines, and cyclic amines, such astromethamine, benzylamines, pyrrolidines, piperidine, morpholine, andpiperazine, and inorganic salts derived from sodium, calcium, potassium,magnesium, manganese, iron, copper, zinc, aluminum, and lithium.

Solvates

In other embodiments, the invention provides a solvate of a compound ofFormula (I), and the use of such solvates in methods of presentinvention. Certain compounds of Formula (I) or pharmaceuticallyacceptable salts of compounds of Formula (I) may be obtained assolvates. In some embodiments, the solvent is water and the solvates arehydrates.

More particularly, solvates include those formed from the interaction orcomplexes of compounds of the invention with one or more solvents,either in solution or as a solid or crystalline form. Such solventmolecules are those commonly used in the pharmaceutical art, which areknown to be innocuous to the recipient, e.g., water, ethanol, ethyleneglycol, and the like. Other solvents may be used as intermediatesolvates in the preparation of more desirable solvates, such as MeOH,methyl t-butyl ether, ethyl acetate, methyl acetate, (S)-propyleneglycol, (R)-propylene glycol, 1,4-butyne-diol, and the like. Hydratesinclude compounds formed by an incorporation of one or more watermolecules.

Conformers and Crystalline Forms/Polymorphs

In other embodiments, the invention provides conformer and crystallineform of a compound of Formula (I), and the use of these derivatives inmethods of present invention. A conformer is a structure that is aconformational isomer. Conformational isomerism is the phenomenon ofmolecules with the same structural formula but different conformations(conformers) of atoms about a rotating bond.

A polymorph is a composition having the same chemical formula, but adifferent solid state or crystal structure. In certain embodiments ofthe invention, compounds of Formula (I) were obtained in crystallineform. In addition, certain crystalline forms of compounds of Formula (I)or pharmaceutically acceptable salts of compounds of Formula (I) may beobtained as co-crystals. In still other embodiments, compounds ofFormula (I) may be obtained in one of several polymorphic forms, as amixture of crystalline forms, as a polymorphic form, or as an amorphousform.

Prodrugs

The invention also relates to prodrugs of the compounds of Formula (I),and the use of such pharmaceutically acceptable prodrugs in methods ofthe present invention, particularly therapeutic methods. Exemplaryprodrugs include compounds having an amino acid residue, or apolypeptide chain of two or more (e.g., two, three or four) amino acidresidues, covalently joined through an amide or ester bond to a freeamino, hydroxy, or carboxylic acid group of a compound of Formula (I).Examples of amino acid residues include the twenty naturally occurringamino acids, commonly designated by three letter symbols, as well as4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvalin, beta-alanine, gamma-aminobutyric acid,citrulline homocysteine, homoserine, ornithine and methionine sulfone.

Additional types of prodrugs may be produced, for instance, byderivatizing free carboxyl groups of structures of Formula (I) as amidesor alkyl esters. Examples of amides include those derived from ammonia,primary C₁₋₆alkyl amines and secondary di(C₁₋₆alkyl) amines. Secondaryamines include 5- or 6-membered heterocycloalkyl or heteroaryl ringmoieties. Examples of amides include those that are derived fromammonia, C₁₋₃alkyl primary amines, and di(C₁₋₂alkyl)amines. Examples ofesters of the invention include C₁₋₆alkyl, C₁₋₆cycloalkyl, phenyl, andphenyl(C₁₋₆alkyl) esters. Preferred esters include methyl esters.Prodrugs may also be prepared by derivatizing free hydroxy groups usinggroups including hemisuccinates, phosphate esters,dimethylaminoacetates, and phosphoryloxymethyloxycarbonyls, followingprocedures such as those outlined in Fleisher et al., Adv. Drug DeliveryRev. 1996, 19, 115-130.

Carbamate derivatives of hydroxy and amino groups may also yieldprodrugs. Carbonate derivatives, sulfonate esters, and sulfate esters ofhydroxy groups may also provide prodrugs. Derivatization of hydroxygroups as (acyloxy)methyl and (acyloxy)ethyl ethers, wherein the acylgroup may be an alkyl ester, optionally substituted with one or moreether, amine, or carboxylic acid functionalities, or where the acylgroup is an amino acid ester as described above, is also useful to yieldprodrugs. Prodrugs of this type may be prepared as described in Robinsonet al., J. Med. Chem. 1996, 39, 10-18. Free amines can also bederivatized as amides, sulfonamides or phosphonamides. All of theseprodrug moieties may incorporate groups including ether, amine, andcarboxylic acid functionalities.

Prodrugs may be determined using routine techniques known or availablein the art (e.g., Bundgard (ed.), 1985, Design of prodrugs, Elsevier;Krogsgaard-Larsen et al., (eds.), 1991, Design and Application ofProdrugs, Harwood Academic Publishers).

Metabolites

The present invention also relates to a metabolite of a compound ofFormula (I), as defined herein, and salts thereof. The present inventionfurther relates to the use of such metabolites, and salts thereof, inmethods of present invention, including therapeutic methods.

Metabolites of a compound may be determined using routine techniquesknown or available in the art. For example, isolated metabolites can beenzymatically and synthetically produced (e.g., Bertolini et al., J.Med. Chem. 1997, 40, 2011-2016; Shan et al., J. Pharm. Sci. 1997, 86,765-767; Bagshawe, Drug Dev. Res. 1995, 34, 220-230; and Bodor, Adv DrugRes. 1984, 13, 224-231).

Compositions

In some embodiments Compounds of Formula (I) and pharmaceuticallyacceptable salts thereof are used, alone or in combination with one ormore additional active ingredients, to formulate pharmaceuticalcompositions. A pharmaceutical composition of the invention comprises:(a) an effective amount of at least one active agent in accordance withthe invention; and (b) a pharmaceutically acceptable excipient.

Formulations and Administration

Numerous standard references are available that describe procedures forpreparing various formulations suitable for administering the compoundsaccording to the invention. Examples of potential formulations andpreparations are contained, for example, in the Handbook ofPharmaceutical Excipients, American Pharmaceutical Association (currentedition); Pharmaceutical Dosage Forms: Tablets (Lieberman, Lachman andSchwartz, editors) current edition, published by Marcel Dekker, Inc., aswell as Remington's Pharmaceutical Sciences (Osol, ed.), 1980,1553-1593.

Any suitable route of administration may be employed for providing ananimal, especially a human, with an effective dosage of a compound ofthe present invention. For example, oral, rectal, topical, parenteral,ocular, pulmonary, nasal, and the like may be employed. Dosage formsinclude tablets, troches, dispersions, suspensions, solutions, capsules,creams, ointments, aerosols, and the like.

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water, and the like. The particularcarrier, diluent, or excipient used will depend upon the means andpurpose for which the compound of the present invention is beingapplied. Solvents are generally selected based on solvents recognized bypersons skilled in the art as safe (GRAS) to be administered to ananimal. In general, safe solvents are non-toxic aqueous solvents such aswater and other non-toxic solvents that are soluble or miscible inwater. Suitable aqueous solvents include water, ethanol, propyleneglycol, polyethylene glycols (e.g., PEG400, PEG300), etc. and mixturesthereof. The formulations may also include one or more buffers,stabilizing agents, surfactants, wetting agents, lubricating agents,emulsifiers, suspending agents, preservatives, antioxidants, opaquingagents, glidants, processing aids, colorants, sweeteners, perfumingagents, flavoring agents and other known additives to provide an elegantpresentation of the drug (i.e., a compound of the present invention orpharmaceutical composition thereof) or aid in the manufacturing of thepharmaceutical product (i.e., medicament).

The formulations may be prepared using conventional dissolution andmixing procedures. For example, the bulk drug substance (i.e., acompound of the present invention or stabilized form of the compound(e.g., complex with a cyclodextrin derivative or other knowncomplexation agent)) is dissolved in a suitable solvent in the presenceof one or more of the excipients described above. The compound of thepresent invention is typically formulated into pharmaceutical dosageforms to provide an easily controllable and appropriate dosage of thedrug.

The pharmaceutical composition (or formulation) for application may bepackaged in a variety of ways, depending upon the method used toadminister the drug. Generally, an article for distribution includes acontainer having deposited therein the pharmaceutical formulation in anappropriate form. Suitable containers are well-known to those skilled inthe art and include materials such as bottles (plastic and glass),sachets, ampoules, plastic bags, metal cylinders, and the like. Thecontainer may also include a tamper-proof assemblage to preventindiscreet access to the contents of the package. In addition, thecontainer has deposited thereon a label that describes the contents ofthe container. The label may also include appropriate warnings.

The present compounds may be systemically administered, e.g., orally, incombination with a pharmaceutically acceptable vehicle such as an inertdiluent or an assimilable edible carrier. They may be enclosed in hardor soft shell gelatin capsules, may be compressed into tablets, or maybe incorporated directly with the food of the patient's diet. For oraltherapeutic administration, the active compound may be combined with oneor more excipients and used in the form of ingestible tablets, buccaltablets, troches, capsules, elixirs, suspensions, syrups, wafers, andthe like. Such compositions and preparations should contain at least0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be betweenabout 2 to about 60% of the weight of a given unit dosage form. Theamount of active compound in such therapeutically useful compositions issuch that an effective dosage level will be obtained.

The tablets, troches, pills, capsules, and the like may also contain thefollowing: binders such as gum tragacanth, acacia, corn starch orgelatin; excipients such as dicalcium phosphate; a disintegrating agentsuch as corn starch, potato starch, alginic acid and the like; alubricant such as magnesium stearate; and a sweetening agent such assucrose, fructose, lactose or aspartame or a flavoring agent such aspeppermint, oil of wintergreen, or cherry flavoring may be added. Whenthe unit dosage form is a capsule, it may contain, in addition tomaterials of the above type, a liquid carrier, such as a vegetable oilor a polyethylene glycol. Various other materials may be present ascoatings or to otherwise modify the physical form of the solid unitdosage form. For instance, tablets, pills, or capsules may be coatedwith gelatin, wax, shellac or sugar and the like. A syrup or elixir maycontain the active compound, sucrose or fructose as a sweetening agent,methyl and propylparabens as preservatives, a dye and flavoring such ascherry or orange flavor. Of course, any material used in preparing anyunit dosage form should be pharmaceutically acceptable and substantiallynon-toxic in the amounts employed. In addition, the active compound maybe incorporated into sustained-release preparations and devices.

The active compound may also be administered intravenously orintraperitoneally by infusion or injection. Solutions of the activecompound or its salts can be prepared in water, optionally mixed with anontoxic surfactant. Dispersions can also be prepared in glycerol,liquid polyethylene glycols, triacetin, and mixtures thereof and inoils. Under ordinary conditions of storage and use, these preparationscontain a preservative to prevent the growth of microorganisms.

The pharmaceutical dosage forms suitable for injection or infusion caninclude sterile aqueous solutions or dispersions or sterile powderscomprising the active ingredient which are adapted for theextemporaneous preparation of sterile injectable or infusible solutionsor dispersions, optionally encapsulated in liposomes. In all cases, theultimate dosage form should be sterile, fluid, and stable under theconditions of manufacture and storage. The liquid carrier or vehicle canbe a solvent or liquid dispersion medium comprising, for example, water,ethanol, a polyol (for example, glycerol, propylene glycol, liquidpolyethylene glycols, and the like), vegetable oils, nontoxic glycerylesters, and suitable mixtures thereof. The proper fluidity can bemaintained, for example, by the formation of liposomes, by themaintenance of the required particle size in the case of dispersions orby the use of surfactants. The prevention of the action ofmicroorganisms can be brought about by various antibacterial andantifungal agents, for example, parabens, chlorobutanol, phenol, sorbicacid, thimerosal, and the like. In many cases, it will be preferable toinclude isotonic agents, for example, sugars, buffers or sodiumchloride. Prolonged absorption of the injectable compositions can bebrought about by the use in the compositions of agents delayingabsorption, for example, aluminum monostearate and gelatin.

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent with avariety of the other ingredients enumerated above, as required, followedby filter sterilization. In the case of sterile powders for thepreparation of sterile injectable solutions, common methods ofpreparation are vacuum drying and the freeze drying techniques, whichyield a powder of the active ingredient plus any additional desiredingredient present in the previously sterile-filtered solutions.

For topical administration, the present compounds may be applied in pureform, i.e., when they are liquids. However, it will generally bedesirable to administer them to the skin as compositions orformulations, in combination with a dermatologically acceptable carrier,which may be a solid or a liquid.

Useful solid carriers include finely divided solids such as talc, clay,microcrystalline cellulose, silica, alumina, and the like. Useful liquidcarriers include water, alcohols or glycols or water-alcohol/glycolblends, in which the present compounds can be dissolved or dispersed ateffective levels, optionally with the aid of non-toxic surfactants.Adjuvants such as fragrances and additional antimicrobial agents can beadded to optimize the properties for a given use. The resultant liquidcompositions can be applied from absorbent pads, used to impregnatebandages and other dressings, or sprayed onto the affected area usingpump-type or aerosol sprayers.

Thickeners such as synthetic polymers, fatty acids, fatty acid salts andesters, fatty alcohols, modified celluloses or modified mineralmaterials can also be employed with liquid carriers to form spreadablepastes, gels, ointments, soaps, and the like, for application directlyto the skin of the user.

Dosages

Useful dosages of the compounds of Formula (I) can be determined bycomparing their in vitro activity and in vivo activity in animal models.Methods for the extrapolation of effective dosages in mice, and otheranimals, to humans are known to the art. Useful dosages of the compoundsof formula I can be determined by comparing their in vitro activity, andin vivo activity in animal models. Methods for the extrapolation ofeffective dosages in mice, and other animals, to humans are known to theart (e.g., U.S. Pat. No. 4,938,949). Useful dosages of MAO-B inhibitorsare known to the art (e.g., U.S. 2007-0203154, U.S. 2011-0160248, U.S.2010-0317648, and U.S. Pat. No. 8,222,243).

Optimal dosages to be administered in the therapeutic methods of thepresent invention may be determined by those skilled in the art and willdepend on multiple factors, including the particular composition in use,the strength of the preparation, the mode and time of administration,and the advancement of the disease or condition. Additional factors mayinclude characteristics on the subject being treated, such as age,weight, gender, and diet.

In general, however, a suitable dose will be in the range from about0.01 to about 100 mg/kg, more specifically, from about 0.1 to about 100mg/kg, such as 10 to about 75 mg/kg of body weight per day, 3 to about50 mg per kilogram body weight of the recipient per day, 0.5 to 90mg/kg/day, or 1 to 60 mg/kg/day (or any other value or range of valuestherein). The compound is conveniently administered in a unit dosageform; for example, containing about 1 to 1000 mg, particularly about 10to 750 mg, and more particularly, about 50 to 500 mg of activeingredient per unit dosage form.

Preferably, the active ingredient should be administered to achieve peakplasma concentrations of the active compound of from about 0.5 to about75 μM, preferably, about 1 to 50 μM, and more preferably, about 2 toabout 30 μM. This may be achieved, for example, by the intravenousinjection of a 0.05 to 5% solution of the active ingredient, optionallyin saline, or orally administered as a bolus containing about 1 to 100mg of the active ingredient. Desirable blood levels may be maintained bycontinuous infusion to provide about 0.01 to 5.0 mg/kg/hr or byintermittent infusions containing about 0.4 to 15 mg/kg of the activeingredient(s).

The desired dose may conveniently be presented in a single dose or asdivided doses administered at appropriate intervals, for example, astwo, three, four or more sub-doses per day. The sub-dose itself may befurther divided, e.g., into a number of temporally-distinctadministrations used according to the compositions and methods of thepresent invention.

Effective amounts or doses of the active agents of the present inventionmay be ascertained by routine methods such as modeling, dose escalationstudies or clinical trials, and by taking into consideration routinefactors, e.g., the mode or route of administration or drug delivery, thepharmacokinetics of the agent, the severity and course of the disease,disorder, or condition, the subject's previous or ongoing therapy, thesubject's health status and response to drugs, and the judgment of thetreating physician. Such compositions and preparations should contain atleast 0.1% of active compound. The percentage of the compositions andpreparations may, of course, be varied and may conveniently be between 2to about 60% of the weight of a given unit dosage form. The amount ofactive compound in such therapeutically useful composition is such thatan effective dosage level will be obtained. An exemplary dose is in therange from about 0.001 to about 200 mg of active agent per kg ofsubject's body weight per day, preferably about 0.05 to 100 mg/kg/day,or about 1 to 35 mg/kg/day, or about 0.1 to 10 mg/kg/daily in single ordivided dosage units (e.g., BID, TID, QID). For a 70-kg human, anillustrative range for a suitable dosage amount is from 1 to 200 mg/day,or about 5 to 50 mg/day.

Methods and Uses

Uses of Isotopically-Labeled Compounds

In one aspect, the present invention provides a method of usingisotopically labeled compounds and prodrugs of the present invention in:(i) metabolic studies (preferably with ¹⁴C), reaction kinetic studies(with, for example ²H or ³H); (ii) detection or imaging techniques [suchas positron emission tomography (PET) or single-photon emission computedtomography (SPECT)] including drug or substrate tissue distributionassays; or (iii) in radioactive treatment of patients.

Isotopically labeled compounds and prodrugs of the invention thereof cangenerally be prepared by carrying out the procedures disclosed in theschemes or in the examples and preparations described below bysubstituting a readily available isotopically labeled reagent for anon-isotopically labeled reagent. An ¹⁸F or ¹¹C labeled compound may beparticularly preferred for PET, and an I¹²³ labeled compound may beparticularly preferred for SPECT studies. Further substitution withheavier isotopes such as deuterium (i.e., ²H) may afford certaintherapeutic advantages resulting from greater metabolic stability, forexample increased in vivo half-life or reduced dosage requirements.

Therapeutic Methods

Generally

In certain embodiments the present invention provides therapeuticmethods of using a compound of Formula (I) and its pharmaceuticallyacceptable salts, pharmaceutically acceptable prodrugs, andpharmaceutically active metabolites, whether alone or in combination(collectively, “active agents”) of the present invention are useful asinhibiting MAO in the methods of the invention. Such methods forinhibiting MAO, comprising administering to an animal an effectiveamount of at least one chemical entity selected from compounds ofFormula (I), pharmaceutically acceptable salts of compounds of Formula(I), pharmaceutically acceptable prodrugs of compounds of Formula (I),and pharmaceutically active metabolites of compounds of Formula (I).Embodiments of this invention inhibit MAO. The invention furtherincludes the use of such compounds and compositions thereof in themethods described herein. In one aspect of such methods disclosedherein, the animal is healthy. In another aspect of such methods, theanimal has a disorder. In another aspect of all such methods the animalis an aged animal. In preferred embodiments the animal in such methodsis a human.

In one aspect, such chemical entities are useful as inhibitors ofmonoamine oxidase, and monoamine oxidase type B selectively.Accordingly, the present invention provides a method for inhibiting MAO,comprising administering to an animal an effective amount of a chemicalentity of Formula (I) or composition thereof.

Chemical entities of the present invention may be administered as amonotherapy or as part of a combination therapy. In one aspect, one ormore of the compounds (or salts, produgs, or metabolites thereof) of thepresent invention may be co-administered or used in combination with oneor more additional therapies known in the art. For example, compounds ofthe present invention may be used as adjunct therapy with dopaminepreparations, dopamine agonists, or COMT agents (drugs that inhibit theaction of catechol-methyl transferase) for the treatment of Parkinson'sdisease. As another example, targeting both monoamine oxidase-Binhibition and iron chelation can confer superior neuroprotectionagainst Parkinson's disease and other neurodegenerative disorders (e.g.,Youdim et al., J. Neural. Transm. 2004, 111, 1455-1471).

The present invention also includes methods of treating a disease,disorder, or condition mediated by MAO. Accordingly, in one embodiment,the invention provides a method of treating a disorder mediated by MAO,and MAO-B in particular, comprising administering to an animal in needof such treatment an effective amount of a chemical entity of Formula(I) or composition of the present invention.

In certain embodiments, the present invention includes the use of achemical entity of Formula (I) in the manufacture of a medicament fortreating a disease, condition, or disorder by inhibiting MAO-B. Thepresent invention further provides a method of administering atherapeutically effective amount of a medicament of the presentinvention to a patient in need of such treatment to treat the disorder.

In one aspect, the compounds of the present invention are useful inenhancing neuronal plasticity—an essential property of the brain thatcan be augmented in healthy animals and can be impaired in numerous CNSdisorders. For example, by inhibiting MAO-B activity, a compound of thepresent invention may enhance levels of Ca²⁺ and cAMP/cGMP, triggering asignaling cascade that ultimately activates transcription factors,including the cAMP responsive element binding protein (CREB). CREBactivation can then increase expression of neuronal plasticity-relatedgenes, neurotrophic factors, and neuroprotective molecules—which in turncan promote the functional and morphological changes necessary forneuronal plasticity to occur (e.g., Tully et al., Nat. Rev. Drug.Discov. 2003, 2, 267-277; and Alberini, Physiol. Rev. 2009, 89,121-145). Indeed, compounds of the present invention have been shown toactivate CREB in cell-based assays. Accordingly, the present inventionprovides a method of enhancing neuronal plasticity, comprisingadministering to an animal in need thereof an effective amount of achemical entity or composition of the present invention.

In another embodiment, the present invention provides a method oftreating a disease mediated by MAO, comprising administering to ananimal in need of such treatment an effective amount of a compound orcomposition of the present invention. MAO-B related indications that canbe treated by compounds and compositions of the present inventioninclude, but are not limited to neurological disorders, endocrine ormetabolic disorders; and other disorders involving MAO-B signaling.

Chemical entities and compositions of the present invention are alsouseful as neuroprotective agents, as described in greater detail herein.Accordingly, the present invention provides a method of neuroprotection,comprising administering to an animal in need thereof an effectiveamount of at least one chemical entity or composition of the presentinvention.

Chemical entities and compositions of the present invention are alsouseful as agents in neurorehabilitation and neurorecovery, as describedin greater detail herein. Accordingly, the present invention provides amethod of neurorehabilitation or neurorecovery, comprising administeringto an animal in need thereof an effective amount of at least onechemical entity or composition of the present invention.

In addition, such compounds can be administered in conjunction withtraining protocols to treat cognitive or motor deficits associated withCNS disorders, as described in more detail herein. In addition, suchcompounds can be used to enhance the efficiency of training protocols innon-human animals, in particular healthy non-human animals, as describedherein.

Neurological Disorders

In some embodiments, the present invention provides a method of treatinga neurological disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or compositiondescribed herein.

A neurological disorder (or condition or disease) is any disorder of thebody's nervous system. Neurological disorders can be categorizedaccording to the primary location affected, the primary type ofdysfunction involved, or the primary type of cause. The broadestdivision is between central nervous system (CNS) disorders andperipheral nervous system (PNS) disorders.

Neurological disorders include structural, biochemical, or electricalabnormalities in the brain, spinal cord or other nerves, abnormalitiesthat can result in a range of symptoms. Examples of such symptomsinclude paralysis, muscle weakness, poor coordination, loss ofsensation, seizures, confusion, pain, altered levels of consciousness,and cognitive deficits, including memory impairments. There are manyrecognized neurological disorders, some relatively common, but manyrare. They may be assessed by neurological examination, and studied andtreated within the specialties of neurology and clinicalneuropsychology.

Neurological disorders and their sequelae (direct consequences) affectas many as one billion people worldwide, as estimated by the WorldHealth Organization in 2006. Interventions for neurological disordersmay include, in addition to medications, preventative measures,lifestyle changes, physiotherapy or other therapies,neurorehabilitation, pain management, and surgery.

Neurological disorders include, but are not limited to the following(which are not necessarily mutually exclusive): psychiatric disorders,such as mood disorders, psychotic disorders, and anxiety disorders;personality disorders; substance-related disorders; dissociativedisorders; eating disorders; sleep disorders; developmental disorders;neurodegenerative disorders, including movement disorders;trauma-related disorders; pain disorders; and cognitive disorders, acategory that includes memory disorders such as AAMI and MCI, as well ascognitive deficits (particularly memory deficits) associated with CNSdisorders.

Psychiatric Disorders

In one embodiment, the invention provides a method of treating apsychiatric disorder, comprising administering to an animal in need ofsuch treatment an effective amount of a compound or pharmaceuticalcomposition described herein. Psychiatric disorders include mood (oraffective) disorders, psychotic disorders, and anxiety (or neurotic)disorders (e.g., Liebowitz et al., “Reversible and irreversiblemonoamine oxidase inhibitors in other psychiatric disorders”, Acta.Psychiatr. Scand. Suppl. 1990, 360, 29-34.

Mood Disorders

In some embodiments, the psychiatric disorder is a mood (or affective)disorder. Accordingly, the present invention provides a method oftreating a mood disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or pharmaceuticalcomposition described herein. In a specific aspect, the mood disorder isa depressive disorder, including a dysthymic disorder, major depressivedisorder (recurrent and single episode), mania, bipolar disorders (I andII), and cyclothymic disorder. Long-standing research underscores a rolefor MAO in mood disorders, including depressive disorders, bipolardisorders, and substance induced mood disorders is known in theliterature (e.g., Gutierrez B, et al., “Association analysis between afunctional polymorphism in the monoamine oxidase A gene promoter andsevere mood disorders”, Psychiatr. Genet. 2004, 14, 203-208; Duncan etal., “Monoamine oxidases in major depressive disorder and alcoholism”,Drug Discover. Ther. 2012, 6, 112-122.

A specific embodiment of the invention is a method of treating asubstance induced mood disorder, comprising administering to an animalin need of such treatment a therapeutically effective amount of acompound or pharmaceutical composition described herein. The utility ofMAO inhibitors in the treatment of substance induced mood disorders isknown in the literature (e.g., Takahashi et al., “Monoamine oxidaseactivity in blood platelets in alcoholism.” Folia. Psychiatr. Neurol.Jpn. 1976, 30, 455-462).

Psychotic Disorders

In some embodiments, the psychiatric disorder is a psychotic disorder.Accordingly, the present invention provides a method of treating apsychotic disorder, comprising an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. In a specific aspect, the psychotic disorder is one or more ofthe following: schizophrenia; schizophreniform disorder; schizoaffectivedisorder; delusional disorder; brief psychotic disorder; sharedpsychotic disorder; substance-induced psychotic disorders, such as apsychosis induced by alcohol, amphetamine, cannabis, cocaine,hallucinogens, inhalants, opioids, or phencyclidine; and personalitydisorders at times of stress (including paranoid personality disorder,schizoid personality disorder, and borderline personality disorder).

A specific embodiment of the invention is a method of treating adelusional disorder, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of MAOinhibitors in the treatment of delusional disorders is known in theliterature (e.g., DeVane and Mintzer, “Risperidone in the management ofpsychiatric and neurodegenerative disease in the elderly: an update”,Psychopharmacol. Bull. 2003, 37, 116-132.

A particular embodiment of the invention is a method of treatingschizophrenia, comprising administering to an animal in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of MAOinhibitors in the treatment of schizophrenia, including schizophreniformdisorder and schizoaffective disorder, is known in the literature (e.g.,Toren et al., “Benefit-risk assessment of atypical antipsychotics in thetreatment of schizophrenia and comorbid disorders in children andadolescents”, Drug Saf. 2004, 27, 1135-1156).

Anxiety Disorders

In some embodiments, the psychiatric disorder is an anxiety (orneurotic) disorder. Accordingly, the present invention provides a methodof treating an anxiety disorder, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, theanxiety disorder is one or more of the following: panic disorder,specific phobia, social phobia, obsessive-compulsive disorder,generalized anxiety disorder, post-traumatic stress disorder; and acutestress disorder. The use of MAO inhibitors in the treatment of anxietyis known in the literature (e.g., Galynker et al., “Low-dose risperidoneand queriapine as monotherapy for comorbid anxiety and depression”, J.Clin. Psychiatry 2005, 66, 544).

Personality Disorders

In some embodiments, the neurological disorder is a personalitydisorder. Accordingly, the present invention provides a method oftreating a personality disorder, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In particular embodiments,the personality disorder is one or more of the following: includes thoseof Cluster A (odd or eccentric), such as paranoid or schizoidpersonality disorder; those of Cluster B (dramatic, emotional, orerratic), such as antisocial, borderline, or narcissistic personalitydisorder; and those of Cluster C (anxious or fearful), such as avoidant,dependent, or obsessive-compulsive personality disorder.

Substance Related Disorders

In some embodiments, the neurological disorder is a substance-relateddisorder. Accordingly, a specific embodiment of the invention is amethod of treating a substance-related disorder, comprisingadministering to an animal in need of such treatment an effective amountof a compound or pharmaceutical composition described herein.

More particularly, the substance-related disorder includes one or moreof the following: an alcohol-related disorder, such as abuse,dependence, and withdrawal; an amphetamine (or amphetamine-related)disorder, such as abuse, dependence and withdrawal, a cocaine-relateddisorder, such as abuse, dependence and withdrawal; ahallucinogen-related disorder, such as abuse, dependence and withdrawal;an inhalant-related disorder, such as dependent and withdrawal; anicotine-related disorder, such as dependence and withdrawal; anopioid-related disorder, such as abuse, dependence and withdrawal; aphencyclidine (or phencyclidine-like) related disorder, such as abuseand dependence; and a sedative-, hypnotic-, or anxiolytic-relateddisorder, such as abuse, dependence, and withdrawal (e.g., Melis et al,“The dopamine hypothesis of drug addiction: Hypodopaminergic state”,International Review of Neurobiology 2005, 63, 101-154, 2005; and Volkowet al., “Profound decreases in dopamine release in striatum indetoxified alcoholics: Possible orbitofrontal involvement”, J. Neurosci.2007, 27, 12700-12706.

In a specific embodiment, the compounds and compositions of the presentinvention are useful as an aid to a treatment of smoking cessation.Accordingly, the present invention provides a method of treating smokingaddiction, comprising administering to an animal in need thereof aneffective amount of a compound or composition of the present invention.

Dissociative Disorders

In some embodiments, the neurological disorder is a dissociativedisorder. Accordingly, a specific embodiment of the invention is amethod of treating a dissociative disorder, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, thedissociative disorder includes one or more of the following:depersonalization disorder, dissociative amnesia, and dissociativeidentity disorder.

Eating Disorders

In some embodiments, the neurological disorder is an eating disorder.Accordingly, a specific embodiment of the invention is a method oftreating an eating disorder, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein. More particularly, theeating disorder is anorexia nervosa or bulimia nervosa. The utility ofMAO inhibitors in the treatment of eating disorders is known in theliterature (e.g., Kaplan, Expert Opin. Investig. Drugs. 2003, 12,1441-1443).

Sleep Disorders

In some embodiments, the neurological disorder is a sleep disorder.Accordingly, a specific embodiment of the invention is a method oftreating a sleep disorder, comprising administering to an animal in needof such treatment an effective amount of a compound or pharmaceuticalcomposition described herein. More particularly, the sleep disorderincludes a primary sleep disorder, such as primary hypersomnia, primaryinsomnia, or narcolepsy; a parasomnia, such as a nightmare, or sleepterror disorder; and other sleep disorders. The utility of MAOinhibitors in the treatment of sleep disorders is known in theliterature (e.g., Morgenthaler et al., “Practice parameters for thetreatment of narcolepsy and other hypersomnias of central origins”,Sleep 2007, 30, 1705-1711).

In other embodiments, the sleep disorder is restless leg syndrome.Restless legs syndrome (RLS) is a disorder of the part of the nervoussystem that affects the legs and causes an urge to move them. Peoplewith restless legs syndrome have uncomfortable sensations in their legs(and sometimes arms or other parts of the body) and an irresistible urgeto move their legs to relieve the sensations. The sensations are usuallyworse at rest, especially when lying or sitting. The sensations can leadto sleep deprivation and stress. Because it usually interferes withsleep, it also is considered a sleep disorder. Accordingly, the presentinvention provides a method of treating restless leg syndrome,comprising administering to an animal in need thereof an effectiveamount of a compound or composition of the present invention.

Developmental Disorders

In some embodiments, the neurological disorder is a developmentaldisorder. Accordingly, a specific embodiment of the invention is amethod of treating a developmental disorder, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

More particularly, the developmental disorder is one or more of thefollowing: mental retardation, including mild, moderate, and severeforms; a learning disorder, such as that affecting reading, mathematics,or written expression; a motor skill disorder, such as developmentalcoordination disorder; a communication disorder; a pervasivedevelopmental disorder, such as an autistic disorder, Rhett's disorder,childhood disintegrative disorder, or Asperger's disorder; anattention-deficit or disruptive disorder, such as attention-deficithyperactivity disorder; and a tic disorder, such as Tourette's disorder,chronic motor disorder, or vocal tic disorder.

A specific embodiment of the invention is a method of treating anautistic disorder, comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein. In another embodiment, the inventionprovides a method of treating an attention-deficit hyperactivitydisorder, comprising administering to an animal in need of suchtreatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of MAOinhibitors in the treatment of attention-deficit hyperactivity disorderis known in the literature (e.g., Spencer, “ADHD treatment across thelife cycle”, J. Clin. Psychiatry 2004, 65, 22-26).

Neurodegenerative Disorders

In particular embodiments, the invention provides a method of treating aneurodegenerative disorder, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

In one aspect, neurodegenerative disorders include Alzheimer's disease,Amyotrophic lateral sclerosis, corticobasal degeneration, chronictraumatic encephalopathy, and a disorder associated with repetitive headinjury.

Alzheimer's Disease

In a specific embodiment, the invention provides a method of treatingAlzheimer's disease, comprising administering to an animal in need ofsuch treatment an effective amount of a compound or pharmaceuticalcomposition described herein. A detailed set of criteria for thediagnosis of Alzheimer's is set forth in the Diagnostic and StatisticalManual of Mental Disorders (Fourth Edition, text revision (2000), alsoknown as the DSM-IV-TR). First, multiple cognitive deficits must bepresent, one of which must be memory impairment. Second, one or more ofthe following must be present: aphasia (deterioration of languageabilities); apraxia (difficulty executing motor activities—even thoughmovement, senses, and the ability to understand what is being asked arestill intact); or agnosia (impaired ability to recognize or identifyobjects—even though sensory abilities are intact).

Amyotrophic Lateral Sclerosis

In another specific embodiment, the invention provides a method oftreating amyotrophic lateral sclerosis, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Amyotrophic lateral sclerosis (ALS), often referred to as “Lou Gehrig'sDisease,” is a progressive neurodegenerative disease that affects nervecells. Motor neurons reach from the brain to the spinal cord and fromthe spinal cord to the muscles throughout the body. As motor neuronsdegenerate, they can no longer send impulses to the muscle fibers thatnormally result in muscle movement.

Early symptoms of ALS often include increasing muscle weakness,especially involving the arms and legs, speech, swallowing or breathing.The progressive degeneration of the motor neurons in ALS eventuallyleads to their death. When the motor neurons die, the ability of thebrain to initiate and control muscle movement is lost. With voluntarymuscle action progressively affected, patients in the later stages ofthe disease may become totally paralyzed.

Movement Disorders

In other embodiments, the invention provides a method of treating amovement disorder, comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein. In one aspect, the movement disorderincludes one or more of the following: Huntington's disease, Parkinson'sdisease, an essential tremor, a Lewy body disease, hypokinetic disease,Multiple Sclerosis, various types of Peripheral Neuropathy, dystonia, abasal ganglia disorder, hypokinesia (including akinesia), anddyskinesia. In addition, Tourette's syndrome and other tic disorders canbe included as categories of movement disorders. The utility of MAOinhibitors in the treatment of movement disorders is known in theliterature. (e.g., Waters, “Other pharmacological treatments for motorcomplications and dyskinesias”, Mov. Disord. 2005, 20 Suppl 1 1,S38-S44; and Pearce et al., “The monoamine reuptake blocker brasofensinereverses akinesia without dyskinesia in MPTP-treated and levodopa-primedcommon marmosets”, Mov. Disord. 2002, 17, 877-886).

In related embodiment, the invention provides a method of treatingchorea, comprising administering to an animal in need of such treatmentan effective amount of a compound or pharmaceutical compositiondescribed herein. Chorea can occur in a variety of conditions anddisorders, and is a primary feature of Huntington's disease, aprogressive neurological disorder (e.g., Mann and Chiu, “Plateletmonoamine oxidase activity in Huntington's chorea”, J. Neurol.Neurosurg. Psychiatry 1978, 41, 809-812).

Huntington's Disease

In a specific embodiment, the present invention provides a method oftreating Huntington's disease, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Huntington's Disease (HD, or Huntington chorea) is a disorder passeddown through families in which nerve cells in certain parts of the brainwaste away, or degenerate. It is caused by a genetic defect onchromosome 4, causing a CAG repeat, to occur many more times thannormal. The CAG element is normally repeated 10 to 28 times, but inpersons with Huntington's disease, is repeated 36 to 120 times.

There are two forms of Huntington's disease: adult-onset Huntington'sdisease—which is the most common form and usually begins in the mid 30sand 40s; and early-onset Huntington's disease, which accounts for asmall number of cases and begins in childhood or adolescence.

Symptoms of Huntington's disease include behavioral changes, abnormaland unusual movements, and worsening dementia. Behavioral changes mayinclude behavioral disturbances, hallucinations, irritability,moodiness, restlessness or fidgeting, paranoia, and psychosis. Abnormaland unusual movements include facial movements, such as grimaces; headturning to shift eye position; quick, sudden, sometimes wild jerkingmovements of the arms, legs, face, and other body parts; slow,uncontrolled movements; and unsteady gait. Worsening dementia includes;disorientation or confusion; loss of judgment; loss of memory;personality changes; and speech changes (e.g., Dumas et al., “A reviewof cognition in Huntington's disease”, Front Biosci (Schol Ed) 2013, 5,1-18). The utility of MAO-B inhibitors in treating Huntington's diseaseis known in the art (e.g., Messer et al., “Up-regulation of theisoenzymes MAO-A and MAO-B in the human basal ganglia and pons inHuntington's disease revealed by quantitative enzyme radioautography),Brain Res. 2011, 1370, 204-214).

Parkinson's Disease

In a specific embodiment, the present invention provides a method oftreating Parkinson's disease, comprising administering to an animal inneed of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Parkinson's disease (PD) (also known as Parkinson's, idiopathicparkinsonism, primary parkinsonism, PD, hypokinetic rigid syndrome/HRS,or paralysis agitans) is a degenerative disorder of the central nervoussystem estimated to afflict five million people worldwide. It is aslowly progressive neurological condition, characterized by tremors,stiffness, slowness of movement (bradykinesia) and impaired balance.Dopaminergic neurons decline steadily in PD, with motor symptomsemerging when about 50% of nigral neurons have degenerated (Bernheimeret al., “Brain dopamine and the syndromes of Parkinson and Huntington:clinical, morphological and neurochemical correlations”, J. Neurol. Sci.1973, 20, 415-455). At disease presentation, there is approximately a70-80% loss of striatal dopamine concentration (Fearnley and Lees,“Aging and Parkinson's disease: substantia nigra regional selectivity”,Brain 1991, 114, 2283-2301).

More generally, MAO-B levels increase with age, with post mortem brainsamples showing increases of 41.5 and 30.4% in the putamen and globuspallidus lateralis, respectively, between 60 and 90 years of age (Sauraet al., “Biphasic and region specific MAO-B response to aging in normalhuman brain”, Neurobiol. Aging 1997, 18, 497-507).

Hence MAO-B inhibitors lead to an increase in natural dopamine levels inthe brain as well as an increase in dopamine levels produced fromlevodopa (which is a dopamine precursor and is metabolized to dopamineby aromatic amino acid decarboxylase) and are one of the mainstays inthe treatment of PD.

In another aspect, the invention provides a method of treatingParkinson's disease with a compound or pharmaceutical compositiondescribed herein, along with one or more agents useful in treatingParkinson's diseases, for example, L-DOPA; a dopaminergic agonist; aDOPA decarboxylase inhibitor (DCI); or a catechol-O-methyltransferase(COMT) inhibitor. Also claimed is a pharmaceutical compositioncomprising a compound of formula I and one or more agents known to beuseful in the treatment of Parkinson's.

In another embodiment, the invention provides a method of treatingmyoclonus, Gilles de Ia Tourette's syndrome, dystonia, or tics,comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of MAO inhibitors in the treatment of myoclonus,Tourette's syndrome, dystonia and tics is known in the literature (e.g.,Jankovic and Beach, “Long-term effects of tetrabenazine in hyperkineticmovement disorders”, Neurology 1997, 48, 358-362).

A specific embodiment of the invention is a method of treatingmyoclonus, Gilles de Ia Tourette's syndrome, dystonia, or tics,comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of MAO inhibitors in the treatment of myoclonus,Tourette's syndrome, dystonia and tics is known in the literature (e.g.,Jankovic and Beach, “Long-term effects of tetrabenazine in hyperkineticmovement disorders”, Neurology 1997, 48, 358-362).

In a specific aspect, a movement disorder also includes multiplesclerosis, basal ganglia disorders, hypokinesia, and dyskinesia.

Lewy Body Diseases

In one embodiment, the present embodiment, the invention provides amethod of treating a Lewy Body Disease, comprising administering to ananimal in need of such treatment an effective amount of a compound orcomposition of the present invention. Lewy bodies appear as sphericalmasses that displace other cell components. The two morphological typesare classical (brain stem) Lewy bodies and cortical Lewy bodies. Aclassical Lewy body is an eosinophilic cytoplasmic inclusion consistingof a dense core surrounded by a halo of 10-nm-wide radiating fibrils,the primary structural component of which is alpha-synuclein. Incontrast, a cortical Lewy body is less well defined and lacks the halo.Nonetheless, it is still made up of alpha-synuclein fibrils. CorticalLewy bodies are a distinguishing feature of Dementia with Lewy bodies(DLB), but may occasionally be seen in ballooned neurons characteristicof Pick's disease and corticobasal degeneration, as well as in patientswith other tauopathies.

More particularly, the Lewy Body disorder is selected from the groupconsisting of multiple system atrophy, particularly the Parkinsonianvariant; Parkinson disease without or with dementia (PDD); dementia withLBs (DLB) alone or in association with Alzheimer disease (AD); multiplesystem atrophy, particularly the Parkinsonian variant, as well as Pick'sdisease and corticobasal degeneration.

Multiple Sclerosis

In one embodiment, the present invention provides a method of treating amotor symptom associated with multiple sclerosis (MS), comprisingadministering to animal in need of such treatment an effective amount ofa compound or composition of the present invention. MS is an autoimmune,demyelinating disease that affects the brain and spinal cord of the CNS.It affects women more than men and is most commonly diagnosed betweenages 20 and 40, but can be seen at any age.

MS is caused by damage to the myelin sheath, the protective coveringthat surrounds nerve cells. When this nerve covering is damaged, nervesignals slow down or stop. Because nerves in any part of the brain orspinal cord may be damaged, patients with multiple sclerosis can havesymptoms in many parts of the body. Symptoms vary, because the locationand severity of each attack can be different. Episodes can last fordays, weeks, or months. These episodes alternate with periods of reducedor no symptoms (remissions).

Muscle symptoms associated with MS include loss of balance; musclespasms; numbness, tingling, or abnormal sensation in any area; problemsmoving arms or legs; problems walking; problems with coordination andmaking small movements; tremor in one or more arms or legs; and weaknessin one or more arms or legs.

Basal Ganglia Disorders

In particular embodiments, the present invention provides a method oftreating a basal ganglia disorder. Basal ganglia disorders refer to agroup of physical dysfunctions that occur when the group of nuclei inthe brain known as the basal ganglia fail to properly suppress unwantedmovements or to properly prizzme upper motor neuron circuits to initiatemotor function (Leisman and Mello, Rev. Neurosci. 2013, 24, 9-25).

Increased output of the basal ganglia inhibits thalamocorticalprojection neurons. Proper activation or deactivation of these neuronsis an integral component for proper movement. If something causes toomuch basal ganglia output, then the thalamocortical projection neuronsbecome too inhibited and one cannot initiate voluntary movement. Thesedisorders are known as hypokinetic disorders. However, a disorderleading to abnormally low output of the basal ganglia leads torelatively no inhibition of the thalamocortical projection neurons. Thissituation leads to an inability to suppress unwanted movements. Thesedisorders are known as hyperkinetic disorders (Wichmann and DeLong,Curr. Opin. Neurobiol 1996, 6, 751-758).

Hypokinesia

In particular embodiments, the present invention provides a method oftreating hypokinesia. Hypokinesia refers to decreased bodily movements,and they may be associated with basal ganglia diseases (such asParkinson's disease), mental health disorders and prolonged inactivitydue to illness, amongst other diseases.

More generally, hypokinesia describes a spectrum of disorders,including: (i) Akinesia, which refers to the inability to initiatemovement due to difficulty selecting or activating motor programs in thecentral nervous system. Akinesia is a result of severely diminisheddopaminergic cell activity in the direct pathway of movement and iscommon in severe cases of Parkinson's disease; (ii) Bradykinesia, whichis characterized by slowness of movement and has been linked toParkinson's disease and other disorders of the basal ganglia. Ratherthan being a slowness in initiation (akinesia), bradykinesia describes aslowness in the execution of movement. It is one of the 3 key symptomsof parkinsonism, which are bradykinesia, tremor and rigidity.Bradykinesia is also the cause of what is normally referred to as “stoneface” (expressionless face) among those with Parkinson's; (iii)Freezing, which is characterized by an inability to move muscles in anydesired direction; and (iv) Rigidity, which is characterized by anincrease in muscle tone causing resistance to externally imposed jointmovements; and (v) Postural instability, which is the loss of ability tomaintain an upright posture.

Dyskinesia

In particular embodiments, the present invention provides a method oftreating dyskinesia. Dyskinesia is a movement disorder which consists ofadverse effects including diminished voluntary movements and thepresence of involuntary movements, similar to tics or chorea.

Dyskinesia can be anything from a slight tremor of the hands touncontrollable movement of, most commonly, the upper body but can alsobe seen in the lower extremities. Discoordination can also occurinternally especially with the respiratory muscles and it often goesunrecognized. Dyskinesia is a symptom of several medical disorders,distinguished by the underlying cause and generally corresponding to oneof three types: acute dyskinesia, chronic (or tardive) dyskinesia, andnon-motor dyskinesia.

More specifically, a dyskinesia can include one or more the following:paroxysmal dyskinesias, e.g., primary and secondary paroxysmaldyskinesias; paroxysmal kinesigenic dyskinesias (PKD); paroxysmalnon-kinesigenic dyskinesias (PNKD); paroxysmal exercise-induced(exertion-induced) dyskinesias (PED); and paroxysmal hypnogenicdyskinesias (PHD).

Trauma-Related Disorders

In specific embodiments, the present invention provides a method oftreating a trauma-related disorder, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition of the present invention.

In specific embodiments, trauma-related disorders comprise brain trauma;head trauma (closed and penetrating); head injury; tumors, especiallycerebral tumors affecting the thalamic or temporal lobe head injuries;cerebrovascular disorders (diseases affecting the blood vessels in thebrain), such as stroke, ischemia, hypoxia, and viral infection (e.g.,encephalitis); excitotoxicity; and seizures (e.g., Huang et al.,“Neuroprotective effect of rasagiline, a selective monoamine oxidase-Binhibitor, against closed head injury in the mouse”, Eur. J. Pharmacol.1999, 366, 127-135).

Conditions within the scope of the invention that are amenable toneuroprotection include: Stroke; traumatic brain injury (TB); Dementia;Alzheimer's disease; Parkinson's disease; Huntington's disease; Cerebralpalsy; Post-polio syndrome; Guillain-Barre syndrome, and MultipleSclerosis; and other developmental syndromes, genetic conditions, andprogressive CNS diseases affecting cognitive function, such as autismspectrum disorders, fetal alcohol spectrum disorders (FASD),Rubinstein-Taybi syndrome, Down syndrome, and other forms of mentalretardation.

Pain Disorders

In specific embodiments, the invention provides methods of treatingpain, comprising administering to an animal in need of such treatment aneffective amount of a compound or pharmaceutical composition describedherein. The utility of MAO inhibitors in the treatment of pain is knownin the literature (e.g., Pirildar et al., “A preliminary open-labelstudy of moclobemide treatment of pain disorder”, Psychopharmacol. Bull.2003, S37, 127-134; and Silberstein et al., “Preventive treatment ofTragraine: an overview”, Cephalalgia. 1997, 17, 67-72).

In particular embodiments, the pain disorder includes one or more of thefollowing: dental pain, cancer pain, myofascial pain, perioperativepain, acute pain, chronic pain, posttraumatic pain, trigeminalneuralgia, migraine severe pain, intractable pain, neuropathic pain,post-traumatic pain, cancer pain, non-cancer pain. Pain also encompassesa pain disorder associated with psychological factors, a pain disorderassociated with a general medical condition, and a pain disorderassociated with both psychological factors and a general medicalcondition.

Cognitive Disorders

In particular embodiments of the invention, the neurological disorder isa cognitive disorder. Accordingly, the present invention provides amethod of treating a cognitive disorder, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. The utility of MAOinhibitors in the treatment of cognitive disorders is known in theliterature (e.g., Schneider, “New therapeutic approaches to cognitiveimpairment”, J. Clin. Psychiatry 1998, 59, 8-13; U.S. 2007-0203154, U.S.2011-0160248, U.S. 2010-0317648, and U.S. Pat. No. 8,222,243).

Cognitive disorders can significantly impair social and occupationalfunctioning, adversely impacting the autonomy and quality of life of theaffected individual. An estimated four to five million Americans (about2% of all ages and 15% of those older than 65) have some form and degreeof cognitive impairment (Abrams et al., Merck Manual of Geriatrics,1995, Whitehouse Station (NJ), Medical Services).

Cognitive disorders reflect problems in cognition, i.e., the generalprocesses by which knowledge is acquired, retained and used.Accordingly, cognitive disorders can encompass impairments in suchfunctions as concentration, perception, attention, informationprocessing, learning, memory, or language. Cognitive disorders can alsoencompass impairments in psychomotor learning abilities, which includephysical skills, such as movement and coordination; fine motor skillssuch as the use of precision instruments or tools; and gross motorskills, such as dance, musical, or athletic performance.

Cognitive disorders also encompass impairments in executive functions,which include abilities underlying the planning and execution ofgoal-oriented behaviors. Such abilities include flexibility, i.e., thecapacity for quickly switching to the appropriate mental mode;anticipation and prediction based on pattern recognition; reasoning andproblem-solving; decision making; working memory, i.e., the capacity tohold and manipulate internally- or externally-derived information inreal time; emotional self-regulation, including the ability to recognizeand manage one's emotions for good performance; sequencing, such as theability to dissect complex actions into manageable units and prioritizethem in the right order; and self-inhibition, i.e., the ability towithstand distraction and internal urges.

Cognitive disorders also comprise cognitive impairments (deficits ordysfunctions) that are associated with (due to) to CNS disorders. In oneaspect, a cognitive impairment can be a direct result of a CNS disorder.For example, impairments in speech and language can directly result froma stroke or head-injury that damages the brain regions controllingspeech and language, as in aphasia.

In another aspect, a cognitive impairment is associated with a complexCNS disorder, condition, or disease. For example, a cognitive impairmentcan comprise a deficit in executive control that accompanies autism ormental retardation; a deficit in memory associated with schizophrenia orParkinson's disease; or a cognitive deficit arising from multiplesclerosis. In the case of multiple sclerosis (MS), for example, aboutone-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, or impairedmemory. Such problems typically occur later in the course of MS—althoughin some cases they can occur much earlier, if not at the onset ofdisease.

Cognitive impairments can be due to many, non-exclusive categories ofDNS disorders, including the following (and as described herein):

(1) dementias, such as those associated with Alzheimer's disease,Parkinson's disease; Huntington's disease, Pick's disease,Creutzfeldt-Jakob, AIDS Dementia, and other neurodegenerative disorders;and cognitive disabilities associated with progressive diseasesinvolving the nervous system, such as multiple sclerosis.

(2) psychiatric disorders, which include affective (mood) disorders,such as depression and bipolar disorders; psychotic disorders, such asschizophrenia and delusional disorder; and neurotic and anxietydisorders, such as phobias, panic disorders, obsessive-compulsivedisorder, generalized anxiety disorder; eating disorders; andposttraumatic stress disorders.

(3) developmental syndromes, genetic conditions, and progressive CNSdiseases affecting cognitive function, such as autism spectrumdisorders; fetal alcohol spectrum disorders (FASD); Rubinstein-Taybisyndrome; Down syndrome, and other forms of mental retardation; andmultiple sclerosis.

(4) trauma-dependent losses of cognitive functions, i.e., impairments inmemory, language, or motor skills resulting from brain trauma; headtrauma (closed and penetrating); head injury; tumors, especiallycerebral tumors affecting the thalamic or temporal lobe; cerebrovasculardisorders (diseases affecting the blood vessels in the brain), such asstroke, ischemia, hypoxia, and viral infection (e.g., encephalitis);excitotoxicity; and seizures. Such trauma-dependent losses alsoencompass cognitive impairments resulting from extrinsic agents such asalcohol use, long-term drug use, and neurotoxins, e.g., lead, mercury,carbon monoxide, and certain insecticides (e.g., Duncan et al.,“Monoamine oxidases in major depressive disorder and alcoholism”, DrugDiscover. Ther. 2012, 6, 112-122).

(5) age-associated cognitive deficits, including age-associated memoryimpairment (AAMI; also referred to herein as age-related memoryimpairment (AMI)), and deficits affecting patients in early stages ofcognitive decline, as in Mild Cognitive Impairment (MCI); and

(6) learning, language, or reading disabilities, such as perceptualhandicaps, dyslexia, and attention deficit disorders.

Accordingly, the invention provides a method of treating a cognitiveimpairment associated with a CNS disorder selected from one or more ofthe group comprising: dementias, including those associated withneurodegenerative disorders; psychiatric disorders; developmentalsyndromes, genetic conditions, and progressive CNS diseases and geneticconditions; trauma-dependent losses of cognitive function,age-associated cognitive deficits; and learning, language, or readingdisorders.

Dementias

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with dementia, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Dementias are neurodegenerative diseases characterized by learning andcognitive deficiencies and are typically accompanied by behavioralsymptoms, psychological symptoms and motor symptoms. More particularly,dementia symptoms can include difficulty with many areas of mentalfunction, including emotional behavior or personality, language, memory,perception, and thinking and judgment.

Dementias include, but are not limited to, the following: dementia dueto Alzheimer's disease (with early or late onset), dementia due toParkinson's disease, dementia due to Pick's disease, dementia due toCreutzfeldt-Jakob disease, dementia due to HIV disease, dementia due tohead trauma; dementia due to a vascular disease (“vascular dementia”),Lewy body dementia, fronto-temporal dementia, Pick's disease andcorticobasal degeneration.

In one embodiment, dementia is due to Alzheimer's disease. Accordingly,the present invention provides a method of treating dementia due toAlzheimer's disease, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. The utility of MAO-Binhibitors in the treatment of Alzheimer's disease is known in theliterature (e.g., Ono et al., “Antiparkinsonian agenst haveanti-amyloidogenic activity for Alzheimer's beta-amyloid fibrils invitro”, Neurochem. Int. 2006, 48, 275-285). Accordingly, the inventionprovides a method of treating dementia due to Alzheimer's disease,comprising administering to an animal in need of such treatment atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein.

In another embodiment, dementia is due to Parkinson's disease.Accordingly, the invention provides a method of treating dementia due toParkinson's disease, comprising administering to an animal in need ofsuch treatment a therapeutically effective amount of a compound orpharmaceutical composition described herein. Dementia has been reportedto occur in approximately 20%-60% of individuals with Parkinson'sdisease and is more likely to be present in older individuals or thosewith more severe or advanced disease. The dementia associated withParkinson's disease is characterized by cognitive and motoric slowing;problems with executive functioning, such as planning tasks, organizingprojects, or carrying out goals in the proper sequence; and impairmentin memory retrieval. Declining cognitive performance in individuals withParkinson's disease is frequently exacerbated by depression. The utilityof MAO-B inhibitors in treating Parkinson's disease is known in theliterature (e.g., Weinstock, et al., “A novel cholinesterdas andbrain-selective monoamine oxidase inhibitor for the treatment ofdementia comorbid with depression and Parkinson's disease”, Prog.Neuropsychopharmacol. Biol. Psychiatry 2003, 27, 555-561).

Dementia has been reported to occur in approximately 20%-60% ofindividuals with Parkinson's disease and is more likely to be present inolder individuals or those with more severe or advanced disease. Thedementia associated with Parkinson's disease is characterized bycognitive and motoric slowing, executive dysfunction, and impairment inmemory retrieval. Declining cognitive performance in individuals withParkinson's disease is frequently exacerbated by depression. For areview, Davie, “A review of Parkinson's disease”, Br. Med. Bull. 2008,86, 109-127. The motor symptoms of Parkinson's disease result from thedeath of dopamine-generating cells in the substantia nigra, a region ofthe midbrain; the cause of this cell death is unknown. Early in thecourse of the disease, the most obvious symptoms are movement-related.Four motor symptoms are considered cardinal in PD: shaking (tremors),rigidity, slowness of movement, and postural instability, i.e.,difficulty with walking and gait (e.g., Jankovic, “Parkinson's disease:clinical features and diagnosis”, J. Neurol. Neurosurg. Psychiatr. 2008,79, 368-376). Later, cognitive and behavioral problems may arise, withdementia commonly occurring in the advanced stages of the disease. Othersymptoms include sensory, sleep and emotional problems. PD is morecommon in the elderly, with most cases occurring after the age of 50.

In another aspect, a cognitive impairment is associated with a complexCNS syndrome, condition, or disease. For example, a cognitive impairmentcan comprise a deficit in executive control that accompanies autism ormental retardation; a deficit in memory associated with schizophrenia orParkinson's disease; or a cognitive deficit arising from multiplesclerosis. In the case of multiple sclerosis (MS), for example, aboutone-half of MS patients will experience problems with cognitivefunction, such as slowed thinking, decreased concentration, or impairedmemory. Such problems typically occur later in the course of MS—althoughin some cases they can occur much earlier, if not at the onset ofdisease.

In one aspect, a cognitive impairment can be a direct result of a CNSdisorder. For example, impairments in speech and language can directlyresult from a stroke or head-injury that damages the brain regionscontrolling speech and language, as in aphasia.

Psychiatric Disorders

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with a psychiatric disorder, comprisingadministering to an animal in need of such treatment an effective amountof a compound or pharmaceutical composition described herein.Psychiatric disorders include affective disorders (mood disorders), suchas depression and bipolar disorders; psychotic disorders, such asschizophrenia and delusional disorder; and neurotic and anxietydisorders, such as phobias, panic disorders, obsessive-compulsivedisorder, generalized anxiety disorder, eating disorders, andposttraumatic stress disorders.

Developmental Syndromes, Genetic Disorders, and Progressive Diseases

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with a developmental syndrome, geneticdisorder, or progressive disease, comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In a specific aspect, thecognitive deficit is associated with an autism spectrum disorder; afetal alcohol spectrum disorder (FASD); Rubinstein-Taybi syndrome; Downsyndrome, and other forms of mental retardation; and multiple sclerosis.

Trauma-Related Disorders

In a specific embodiment, the invention provides a method of treating acognitive deficit associated with trauma. Such trauma-dependent lossesof cognitive function include, but are not limited to, those due tocerebrovascular diseases, including stroke and ischemia; brain trauma,including subdural hematoma and brain tumor; traumatic brain injury(TBI) and head injury.

Such trauma-dependent losses also encompass cognitive impairmentsresulting from extrinsic agents such as alcohol use, long-term drug use,and neurotoxins such as lead, mercury, carbon monoxide, and certaininsecticides.

Age-Associated Cognitive Deficits

AAMI

In a specific embodiment, the invention provides a method of treating anage-associated cognitive deficit. In one aspect, the age-associatedcognitive deficit is age-related memory impairment (AAMI). Accordingly,the invention provides a method of treating age-associated memoryimpairment (AAMI), comprising administering to an animal in need of suchtreatment an effective amount of a compound or pharmaceuticalcomposition described herein.

AAMI is a decline in various cognitive abilities, in particular memoryabilities, associated with normal aging. For example, AAMI subjects showa decline in the ability to encode new memories of events or facts, aswell as working memory (Hedden and Gabrieli, “Insights into the agingmind: a view from cognitive neuroscience”, Nat. Rev. Neurosci. 2004, 5,87-96). In addition, AAMI subjects, when compared with age-matchedcontrols, appeared to be impaired in tests of executive functionsassociated with frontal lobe function. These and other studies suggestan important role for frontal lobe dysfunction in the memory loss ofelderly people. More generally, studies comparing the effects of agingon episodic memory, semantic memory, short-term memory and priming findthat episodic memory is especially impaired in normal aging; but sometypes of short-term memory can also be impaired (Nilsson, “Memoryfunction in normal aging”, Acta Neurol. Scand. Suppl. 2003, 179, 7-13)

In general, an AAMI diagnosis identifies persons with subjectively andobjectively evidenced memory loss without cognitive decline impairedenough to warrant the diagnosis of dementia. According to criteriaestablished by the NIH working group (Crook et al., “Age-associatedmemory impairment: proposed diagnostic criteria and measures of clinicaldamage—report of a National Institute of Mental Health work group”,Devel. Neuropsychol. 1986, 2, 261-276) a diagnosis of AAMI includes thefollowing in a person aged 50 or older:

i) the presence of subjective memory decline, e.g., complaints of memoryloss reflected in such everyday problems as difficulty remembering namesof individuals introduced to the subject, misplacing objects, difficultyremembering a list of items to be purchased or a list of tasks to beperformed;

ii) objective evidence of memory loss (e.g., a score at least onestandard deviation below the mean of younger adults in a wellstandardized memory test);

iii) evidence of adequate intellectual function (e.g., a raw score of atleast 32) on the Vocabulary subtest of the Wechsler Adult IntelligenceScale., and

iv) the absence of dementia (or other memory-affecting disease, such asstroke), e.g., based on the Global Deterioration Scale for assessment ofdementia, individuals with AAMI have very mild cognitive decline (level2) (Reisberg et al., “The global deterioration Scale for assessment ofprimary degenerative dementia”, Am. J. Psych. 1982, 139, 1136-1139).

Individuals with AAMI have been shown to have a three-fold greater riskfor development of dementia than individuals who do not meet AAMIcriteria (Goldman and Morris, “Evidence that age-associated memoryimpairment is not a normal variant of aging” Alzheimer Dis. Assoc.Disord. 2002, 15:72-79).

MCI

In a specific embodiment, the invention provides a method of treatingmild cognitive impairment (MCI), comprising administering to an animalin need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

MCI may be diagnosed when an individual's memory declines below thelevel considered normal for that age group. In other words, MCI is acondition in which people face memory problems more often than that ofthe average person their age. These symptoms, however, do not preventthem from carrying out normal activities and are not as severe as thesymptoms for Alzheimer's disease. Symptoms often include misplacingitems, forgetting events or appointments, and having trouble thinking ofdesired words.

According to recent research, MCI has been called the transitional statebetween cognitive changes of normal aging and Alzheimer's disease (AD).Many people who experience mild cognitive impairment are at a high riskof developing Alzheimer's disease. Indeed, research suggests that: about12% of people aged 65 or older diagnosed with MCI go on to developAlzheimer's disease within a year; and that about 40% developAlzheimer's within three years. This is a much higher rate than in thegeneral population, wherein only about 1% of people aged 65 or olderdevelop Alzheimer's each year.

Thus, people with MCI are considered at heightened risk to developAlzheimer's disease. These symptoms, however, do not prevent them fromcarrying out normal activities and are not as severe as the symptoms forAlzheimer's disease. Symptoms often include misplacing items, forgettingevents or appointments, and having trouble thinking of desired words(e.g., Arnáiz and Almkvist, “Neuropsychological features of mildcognitive impairment and preclinical Alzheimer's disease” Acta Neurol.Scand. Suppl. 2003, 179, 34-41). Some patients with MCI, however, neverprogress to AD.

Learning and Related Disabilities

In a specific embodiment, the invention provides a method of treating alearning, language, or reading disability, comprising administering toan animal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein.

Neuroprotection

In specific embodiments, the invention provides a method ofneuroprotection, comprising administering to animal in need thereof aneffective amount of a chemical entity or composition of the presentinvention.

Like neuroplasticity, neuroprotection reflects an endogenousneurobiological process that is central to protection of the nervoussystem. More specifically, neuroprotection refers to the ability to haltor slow the loss of neurons, thereby preventing or slowing diseaseprogression and secondary injuries. In a particular aspect,neuroprotection targets neuronal damage arising from oxidative stressand excitotoxicity—both of which are highly associated with CNSdisorders, despite differences in symptoms or injuries.

The utility of MAO inhibitors in the treatment of neuronal damage isknown in the literature. In addition to neurodegenerative diseases,neuronal damage can also result from other sources of trauma, such ascerebrovascular diseases, including stroke and ischemia; brain trauma,including subdural hematoma and brain tumor; and head injury (e.g.,Dunnett and Björklund, “Prospects for new restorative andneuroprotective treatments in Parkinson's disease”, Nature 1999, 399(6738 Suppl), A32-A39; Anderson, “Oxidative stress in neurodegeneration:cause or consequence?” Nat. Med. 2004, 10 Suppl. S18-S25; Mandel et al.,“Mechanism of neuroprotective action of the anti-Parkinson drugrasagiline and its derivatives”, Brain. Res. 2005, 48, 379-387; andMuresanu et al., “Towards a roadmap in brain protection and recovery”,J. Cell. Mol. Med. 2012, 116, 2861-2871).

Augmented Cognitive and Motor Training

In certain embodiments, a compound or composition herein is used as anaugmenting agent in methods to enhance the efficiency of cognitive ormotor training (collectively “training”). Such enhancement methods arecollectively known as “augmented training,” comprising “augmentedcognitive training” or “augmented motor training.”

Training generally requires multiple sessions to attain the desiredbenefits, for example, to rehabilitate a motor deficit or languagedeficit following stroke. This can be costly and time-consuming,deterring subject compliance and the realization of real world benefitsthat endure over time. The efficiency of such training protocols can beimproved by administering certain agents (known as augmenting agents) inconjunction with the training protocol (e.g., U.S. Pat. No. 7,868,015;U.S. Pat. No. 7,947,731; US 2008-0188525). Augmented training comprisesa specific training protocol for a particular brain function, such asthat underlying declarative memory, performance of a fine motor skill,locomotion, language acquisition, an executive function, etc., and ageneral administration of CREB pathway-enhancing drugs. The trainingprotocol (cognitive or motor training) induces neuronal activity inspecific brain regions and produces improved performance of a specificbrain (cognitive or motor) function.

In some embodiments, the invention provides methods of treating acognitive disorder, and more particularly, methods for improving acognitive deficit associated with a central nervous system (CNS)disorder or condition in an animal, comprising treating the animal withan augmenting agent that enhances CREB pathway function in conjunctionwith cognitive training, wherein the augmenting agent is a compound orcomposition of the present invention. Exemplary compounds of the presentinventions, for example, have been shown to activate CREB in cell-basedassays.

In one aspect, the method comprises: (a) providing cognitive training toa subject in need of treatment of a cognitive deficit under conditionssufficient to produce an improvement in performance by said animal of acognitive function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said cognitive training;repeating steps (a) and (b) one or more times; and (d) reducing thenumber of training sessions sufficient to produce the improvement inperformance, relative to the same improvement in performance produced bycognitive training alone.

In another aspect, the method comprises: (a) providing cognitivetraining to a subject in need of treatment of a cognitive deficit underconditions sufficient to produce an improvement in performance by saidanimal of a cognitive function whose impairment is associated with saidcognitive deficit; (b) administering a compound or composition of thepresent invention to the animal in conjunction with said cognitivetraining; repeating steps (a) and (b) one or more times; and (d)producing a long-lasting improvement in performance of said functionrelative to the improvement in performance of said function produced bycognitive training alone.

In one aspect, a compound or composition of the present invention can beused as an augmenting agent in conjunction with any psychotherapeuticapproach intended to modulate cognitive function in the brain, therebyenhancing the efficacy of such therapy by reducing the number ofsessions necessary to attain benefits.

In another aspect, the cognitive deficit treated by these methods is orincludes memory impairment, and more particularly, a defect in long-termmemory. Long-term memory (LTM) generally comprises two main biologicalproperties. First, formation of long-term memory requires synthesis ofnew proteins. Second, it involves cAMP-responsive transcription and ismediated through the cAMP-response element binding protein (CREB) familytranscription factors. Compounds of the present invention can act asCREB-augmenting agents and are therefore useful in enhancing memoryformation in an animal, and more particularly, transcription-dependentmemory. Indeed, exemplary compounds of the present invention activateCREB in cell-based assays.

In some embodiments, the invention provides methods of treating a motordisorder, and more particularly, methods for improving a motor deficitassociated with a central nervous system (CNS) disorder or condition inan animal comprising treating the animal with an augmenting agent thatenhances CREB pathway function in conjunction with motor training.Methods are also provided herein for providing sustained improvement ina motor deficit associated with a central nervous system (CNS) disorderor condition in an animal in need of said treatment comprisingadministering to the animal a compound or composition of the presentinvention; and detecting said sustained improvement

In one aspect, the method comprises: (a) providing motor training to asubject in need of treatment of a motor deficit under conditionssufficient to produce an improvement in performance by said animal of amotor function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said motor training;repeating steps (a) and (b) one or more times; and (d) reducing thenumber of training sessions sufficient to produce the improvement inperformance, relative to the same improvement in performance produced bymotor training alone.

In another aspect, the method comprises: (a) providing motor training toa subject in need of treatment of a motor deficit under conditionssufficient to produce an improvement in performance by said animal of amotor function whose impairment is associated with said cognitivedeficit; (b) administering a compound or composition of the presentinvention to the animal in conjunction with said motor training;repeating steps (a) and (b) one or more times; and (d) producing along-lasting improvement in performance of said function relative to theimprovement in performance of said function produced by motor trainingalone.

In other embodiments, the invention provides methods for enhancing aspecific aspect of cognitive performance in an otherwise healthy animal(particularly in a human or other mammal or vertebrate) comprising (a)administering to the animal an augmenting agent of the presentinvention; and (b) training the animal under conditions sufficient toproduce an improvement in performance of a particular cognitive task bythe animal. In other embodiments, the present invention provides methodsof enhancing cognitive or motor performance, as well as methods forrepeated stimulation of neuronal activity or a pattern of neuronalactivity, such as that underlying a specific neuronal circuit(s).

Augmenting Agents

Augmenting agents, including the compounds and compositions herein, areable to enhance CREB pathway function. By enhancing CREB pathwayfunction in conjunction with training, such augmented training candecrease the number of training sessions required to improve performanceof a cognitive or motor function, relative to the improvement observedby training alone (e.g., U.S. 2007-0203154, U.S. 2011-0160248, U.S.2010-0317648, and U.S. Pat. No. 8,222,243).

The augmenting agent can be administered before, during or after one ormore of the training sessions. In a particular embodiment, theaugmenting agent is administered before and during each trainingsession. Treatment with an augmenting agent in connection with eachtraining session is also referred to as the “augmenting treatment”.

Training Protocols

Training protocols are generally employed in rehabilitating individualswho have some form and degree of cognitive or motor dysfunction. Forexample, training protocols are commonly employed in strokerehabilitation and in age-related memory loss rehabilitation. Becausemultiple training sessions are often required before an improvement orenhancement of a specific aspect of cognitive (or motor) performance(ability or function) is obtained in the individuals, training protocolsare often very costly and time-consuming. Augmented training methods aremore efficacious and therefore more cost-effective.

For example, human brain injury often results in motor and cognitiveimpairments. While advances in critical care medicine and patientmanagement have led to improvements in patient outcome followingtraumatic brain injury (TBI), there is currently no known treatment toprevent the neuronal cell death and dysfunction that follows TBI.Although multiple treatments have proven neuroprotective in pre-clinicalmodels of TBI, most have failed to show efficacy in humans.

Once a patient is stabilized following TBI, the standard of caredictates extensive motor or cognitive rehabilitation. During thisrehabilitation the patient often regains lost skills, finally resultingin improved functional outcome. It would be beneficial if pharmaceuticaltreatments could be developed to enhance motor or cognitiverehabilitation following TBI, and thus improve functional outcome.

Cognitive and motor training protocols and the underlying principles arewell known in the art (e.g., Allen et al., Parkinsons Dis. 2012, 1-15;Jaeggi et al., Proc. Natl. Acad. Sci. USA 2011, 108, 10081-10086; Cheinet al., Psychon. Bull. Rev. 2010, 17, 193-199; Klingberg, Trends Cogn.Sci. 2010, 14, 317-324; Owen et al., Nature 2010, 465, 775-778; Tsao etal., J. Pain 2010, 11, 1120-1128; Lustig et al., Neuropsychol. Rev.2009, 19, 504-522; Park and Reuter-Lorenz, Ann. Rev. Psych. 2009, 60,173-196; Oujamaa et al., Ann. Phys. Rehabil. Med. 2009, 52, 269-293;Frazzitta et al., Movement Disorders 2009, 8, 1139-1143; Jaeggi et al.,Proc. Natl. Acad. Sci. USA 2008, 105, 6829-6833; Volpe et al.,Neurorehabil. Neural Repair 2008, 22, 305-310; Fischer et al., Top.Stroke Rehab. 2007, 14, 1-12; Jonsdottir et al., Neurorehabil. NeuralRepair 2007, 21, 191-194; Stewart et al., J. Neurol. Sci. 2006, 244,89-95; Krakauer, Curr. Opin. Neurol. 2006, 19, 84-90; Belleville et al.,Dement. Geriatr. Cogn. Disord. 2006, 22, 486-499; Klingberg et al., J.Am. Acad. Child. Adolesc. Psychiatry 2005, 44, 177-186; Dean et al.,Arch. Phys. Med. Rehabil. 2000, 81, 409-417; Whitall et al., Stroke2000, 31, 2390-2395; Hummelsheim and Eickhof, Scand. J. Rehabil. Med.1999, 31, 250-256; Merzenich et al., Science 1996, 271, 77-81; Merzenichet al., Cold Spring Harb. Symp. Quant. Biol. 1996, 61, 1-8; Rider andAbdulahad, Percept. Mot. Skills 1991, 73, 219-224 and Wek and Husak,Percept. Mot. Skills, 1989, 68, 107-113.

Cognitive training protocols are directed to numerous cognitivedimensions, including memory, concentration and attention, perception,learning, planning, sequencing, and judgment. Motor training protocolscan be directed to numerous motor domains, such as the rehabilitation ofarm or leg function after a stroke or head injury. One or more protocols(or modules) underling a training program can be provided to a subject.

In some embodiments, the protocols can be used to treat, orrehabilitate, cognitive or motor impairments in afflicted subjects. Suchprotocols may be restorative or remedial, intended to reestablish priorskills and functions, or they may be focused on delaying or slowingcognitive or motor decline due to neurological disease. Other protocolsmay be compensatory, providing a means to adapt to a cognitive or motordeficit by enhancing function of related and uninvolved brain domains.In other embodiments, the protocols can be used to improve particularskills or cognitive or motor functions in otherwise healthy individuals.For example, a cognitive training program might include modules focusedon delaying or preventing cognitive decline that normally accompaniesaging; here the program is designed to maintain or improve cognitivehealth.

In general, a training protocol (or module) comprises a set of distinctexercises that can be process-specific or skill-based: Process-specifictraining focuses on improving a particular domain such as attention,memory, language, executive function, or motor function. Here the goalof training is to obtain a general improvement that transfers from thetrained activities to untrained activities associated with the samecognitive or motor function or domain. For example, an auditorycognitive training protocol can be used to treat a student with impairedauditory attention. At the end of training, the student should show ageneralized improvement in auditory attention, manifested by anincreased ability to attend to and concentrate on verbal informationpresented in class—and therefore to remember to write down and completehomework assignments. Similarly, a cognitive training protocol may bedirected to impaired executive function in an autistic subject,preventing the subject from carrying out instructions to complete anactivity, such as making a meal, cleaning one's room, or preparing forschool in the morning. Cognitive training allows the subject to focushis attention and concentration and as a result, complete the sequenceof tasks required for such activities.

Skill-based training is aimed at improving performance of a particularactivity or ability. Here the goal of training is to obtain a generalimprovement in the skill or ability. For example, a training protocolmay focus on learning a new language, performing a musical instrument,improving memory, or learning a fine motor skill. The differentexercises within such a protocol will focus on core componentsunderlying the skill Modules for increasing memory, for example, mayinclude tasks directed to the recognition and use of fact, and theacquisition and comprehension of explicit knowledge rules.

Some rehabilitation programs may rely on a single strategy (such ascomputer-assisted cognitive training) targeting either an isolatedcognitive function or multiple functions concurrently. For example, theCogState testing method comprises a customizable range of computerizedcognitive tasks able to measure baseline and change in cognitive domainsunderlying attention, memory, executive function, as well as languageand social-emotional cognition (e.g., Yoshida et al., PloS ON, 2011, 6,e20469; Frederickson et al., Neuroepidemiology 2010, 34, 65-75). Otherrehabilitation programs may use an integrated or interdisciplinaryapproach. Cognitive and motor training programs may involve computergames, handheld game devices, interactive exercises, and may employfeedback and adaptive models.

Neurorehabilitation and Neurorecovery

In other embodiment, the invention further relates to the use ofcompounds and compositions of the present invention in neurorecovery andneurorehabilitation-endogenous neurobiological processes that arecentral to recovery of cognitive and motor impairments of the nervoussystem (e.g., Harkema et al., “Locomotor training: as a treatment ofspinal cord injury and in the progression of neurologic rehabilitation”,Arch. Phys. Med. Rehabil. 2012, 93, 1588-1597; Muresanu et al., “Towardsa roadmap in brain protection and recovery”, J. Cell. Mol. Med. 2012,16, 2861-2871).

Neurorehabilitation or neurorecovery generally refers to a collectionprocess that focuses on aiding a person's recovery from a neurologicaldisorder, or helping that individual to live a more normal, active, andindependent life. For example, the quality of life of a person can begreatly affected by a brain or spinal cord injury, or a medicalcondition which affects the mobility, cognitive functions, or otherphysical or psychological processes that have been affected by changesin the nervous system. The goal of neurorehabilitation is to combatthose changes and improve quality of life by various therapies.

Conditions within the scope of the invention that are treated byneurorehabilitation and neurorecovery include: Stroke; traumatic braininjury (TB); Dementia; Alzheimer's disease; Parkinson's disease;Huntington's disease; Cerebral palsy; Post-polio syndrome;Guillain-Barre syndrome, and Multiple Sclerosis; and other developmentalsyndromes, genetic conditions, and progressive CNS diseases affectingcognitive function, such as autism spectrum disorders, fetal alcoholspectrum disorders (FASD), Rubinstein-Taybi syndrome, Down syndrome, andother forms of mental retardation.

By focusing on all aspects of a person's well-being, neurorehabilitationor neurorecovery offers a series of therapies from the psychological tooccupational, teaching or re-training patients on mobility skills,communication processes, and other aspects of that person's dailyroutine. Neurorehabilitation or neurorecovery also provides focuses onnutrition, psychological, and creative parts of a person's recovery.

In one embodiment, the present invention provides a method of augmentingneurorehabilitation or neurorecovery from a cognitive impairment,comprising (a) providing cognitive training to a subject in need oftreatment of a cognitive deficit under conditions sufficient to producean improvement in performance by said animal of a cognitive functionwhose impairment is associated with said cognitive deficit; (b)administering a compound or composition of the present invention to theanimal in conjunction with said cognitive training; repeating steps (a)and (b) one or more times; and (d) producing a long-lasting improvementin performance of said function relative to the improvement inperformance of said function produced by cognitive training alone.

In another embodiment, the present invention provides a method ofaugmenting neurorehabilitation or neurorecovery from a motor impairment,comprising: (a) providing motor training to a subject in need oftreatment of a motor deficit under conditions sufficient to produce animprovement in performance by said animal of a motor function whoseimpairment is associated with said cognitive deficit; (b) administeringa compound or composition of the present invention to the animal inconjunction with said motor training; repeating steps (a) and (b) one ormore times; and (d) reducing the number of training sessions sufficientto produce the improvement in performance, relative to the sameimprovement in performance produced by motor training alone.

Non-Human Animal Training Protocols

Aside from applications for humans, compounds and compositions of thepresent invention have additional uses for non-human animals, namely inenhancing (augmenting) the efficiency of training protocols directed tonumerous cognitive and motor functions.

Conditions, under which non-human animals would benefit, includeenhanced (augmented) training procedures for specific purposes, (e.g.hunting dogs, guide dogs, police dogs etc, or animals used in movieindustry).

Enhanced training protocols can also benefit animals that have beenexposed to stressful or traumatic conditions and are in need of trainingto treat the resulting cognitive impairments. Such a need may arise, forexample, after such an animal has been captured or transported,subjected to new housing conditions (as in a change of domicile orowner), or has developed analogous disorders and is distressed oraggressive, or displays stereotypic behavior, obsessive-compulsivebehavior, or anxiety. Animals which are subject to stress would alsoinclude animals used in racing (eg. dogs, horses, camels) or othersports, performing animals (such as circus animals and those appearingon stage, television or in the movies) and horses that perform dressageand other highly disciplined routines.

Compounds of the present invention can also enhance the efficiency ofrehabilative protocols following physical injury to a non-human animal,such as limb amputation. For example, administering an augmenting agentof the present invention in conjunction with a training protocol canincrease the efficiency of a rehabilitative program by decreasing thenumber of training sessions necessary to achieve an improvement in motorfunction.

In particular embodiments, compounds and compositions of the presentinvention are used in methods of training service animals. By combiningaugmenting agents of the present invention with training protocols, theefficiency of training non-human animals for service in both the publicand private sectors will be enhanced. Service animals are typicallydogs. However, other non-human animals can also be trained to performservices, such as assisting blind or disabled people. For example,miniature horses can be trained to guide the blind, to pull wheelchairs,or to provide support for Parkinson's patients. As another example,capuchin monkeys can be trained to assist disabled perform manual tasks,such as grasping items, operating knobs and switches, turning the pagesof a book.

In specific embodiments, augmented training with compounds andcompositions of the present invention can be used to reduce the numberof training sessions necessary to teach an animal skills that are usefulin public service, such as in law enforcement. In dogs, for example,such skills include, but are not limited to, the following: (i) publicorder maintenance, e.g., chasing, holding, or detaining suspects; (ii)search and rescue, e.g., locating suspects, missing persons, or objects;and (iii) contraband detection, e.g., detecting illicit substances suchas drugs, narcotics, explosives, weapons, and even human remains. Suchmethods can therefore be applied to police dogs, bomb-sniffing dogs,drug-sniffing dogs, search and rescue dogs, etc.

In other embodiments, augmented training (with compounds andcompositions of the present invention) can be used to reduce the numberof training sessions required to teach animals skills that are useful inthe private sector, such as security and medical care. In dogs, forexample, such skills can include, but are not limited to, the following:(i) private security, e.g., guarding property or protecting anindividual; (ii) handicap assistance, e.g., providing eyes for thevisually impaired, ears for the hearing-impaired, arms and legs for thephysically-disabled; (iii) health care, e.g., detecting cancer oraltering a caregiver to seizures in a subject; (iv) psychiatricassistance, e.g., calming a phobic person under stress-triggeringconditions, or alerting an autistic person to distracting repetitivemovements such as hand flapping; and (v) pest control, e.g., identifyingsource of infestations by bedbugs or termites.

In some embodiments, the training protocol can be directed to a singleskill or task, such as the detection of a single drug. In otherembodiments, the training protocol can be directed to a complex set ofskills, such as those underlying search and rescue. For a complex set ofskills, training will therefore comprise more than one task.

In another aspect, when training is carried out with a wide enough scopeof tasks, a generalized “rehabilitation” effect is expected, resultingin generalized improved function of one or more cognitive domains. Thisresults in improved performance of the animal of related tasks(involving the same cognitive domains) that are not specifically part ofthe training protocol.

Accordingly, the present invention provides a method of reducing thetime necessary to teach an animal one or more skills, wherein saidreducing comprising: a) administering an augmenting agent of the presentinvention to the animal; b) providing a training protocol to said dogunder conditions to improve performance of one or more tasks, whereinsaid training protocol comprises multiple training sessions; and c)decreasing the number of training sessions required to improveperformance of said one or more tasks relative to the number of saidtraining sessions required to produce said improvement in performance bythe training protocol alone.

The training protocol can be provided to the animal under conditions toimprove performance of a single task; a complex set of tasks; or a widescope of tasks, resulting in generalized improved function of one ormore cognitive domains. The tasks can relate to a skill involved inpublic service, such as public order maintenance, search and rescue, andcontraband detection. The tasks can also relate to a skill involved inprivate service, such as private security, handicap assistance, healthcare, psychiatric assistance, and pest control.

Peripheral Disorders

MAO-B enzymes are located in a number of peripheral tissues, includingadipose tissues, muscle, and liver. Thus, in one embodiment, theinvention provides a method of treating a peripheral disorder associatedwith MAO-B, by administering to an animal in need thereof atherapeutically effective amount of a compound or pharmaceuticalcomposition described herein.

Obesity, Diabetes, and Cardiometabolic Disorders

MAO-B inhibitors have been shown to reduce the amount of adipose tissue(i.e., body fat) in mammals (e.g., U.S. Pat. No. 8,138,209). Thus, inone embodiment, the invention provides a method of preventing orreversing the deposition of adipose tissue, by administering to ananimal in need thereof a therapeutically effective amount of a compoundor pharmaceutical composition described herein.

By preventing or reversing the deposition of adipose tissue, MAO-Binhibitors can also reduce the incidence or severity of obesity,diabetes, and cardiometabolic disorders. Accordingly, the inventionprovides a method of treating obesity, diabetes, or a cardiometabolicdisorder, or a combination thereof, comprising administering to ananimal in need of such treatment an effective amount of a compound orpharmaceutical composition described herein. In specific embodiments,the cardiometabolic disorder is selected from hypertension,dyslipidemias (e.g., undesired blood lipid levels, elevated cholesterollevels, and lowered LDL levels), high blood pressure, and insulinresistance.

A specific embodiment of the invention is a method of treating obesityin a mammal in need of such treatment, comprising administering to themammal a therapeutically effective amount of a compound orpharmaceutical composition described herein (e.g., Visentin et al.,“Alteration of amine oxidase activity in the adipose tissue of obesesubjects.” Obes. Res. 2004, 12, 547-55).

Comorbidities

Moreover, by reducing the incidence or severity of obesity, diabetes,and cardiometabolic disorders, MAO-B inhibitors reduce the incidence orseverity of associated comorbidities. Accordingly, the inventionprovides a method of treating a comorbidity associated with obesity,diabetes, or a cardiometabolic disorder, or a combination thereof, in amammal in need of such treatment, comprising administering to the mammala therapeutically effective amount of a compound or pharmaceuticalcomposition described herein. In specific embodiments, the comorbidityis a comorbidity of obesity, which includes diabetes, MetabolicSyndrome, dementia, cancer, and heart disease.

EXAMPLES

The present disclosure will be further illustrated by the followingnon-limiting Examples. These Examples are understood to be exemplaryonly, and they are not to be construed as limiting the scope of theinvention herein, and as defined by the appended claims.

Preparative Examples

Exemplary compounds useful in methods of the invention will now bedescribed by reference to the illustrative synthetic schemes for theirgeneral preparation below and the specific examples to follow.

Synthetic Schemes

One skilled in the art will recognize that, to obtain the variouscompounds herein, starting materials may be suitably selected so thatthe ultimately desired substituents will be carried through the reactionscheme with or without protection as appropriate to yield the desiredproduct. Alternatively, it may be necessary or desirable to employ, inthe place of the ultimately desired substituent, a suitable group thatmay be carried through the reaction scheme and replaced as appropriatewith the desired substituent. Unless otherwise specified, the variablesare as defined above in reference to Formula (I). Reactions may beperformed between −78° C. and the reflux temperature of the solvent.Reactions may be heated employing conventional heating or microwaveheating. Reactions may also be conducted in sealed pressure vesselsabove the normal reflux temperature of the solvent.

According to Scheme A, ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate(VIII) is obtained in four steps from commercially availablesynthetically accessible m-anisidine (II). m-Anisidine is combined withdiethyl ethoxymethylenemalonate at temperatures ranging from 100° C. toabout 125° C., preferably 125° C. for a period of 1 to 5 h, preferablyabout 3 h to provide diethyl2-(((3-methoxyphenyl)amino)methylene)malonate. Ethyl4-hydroxy-7-methoxyquinoline-3-carboxylate (III) is obtained by heatingDowtherm™ at a temperature of 257° C. and diethyl2-(((3-methoxyphenyl)amino)methylene)malonate for a period of 15 minutesto 2 h. Compound (IV) ethyl 7-methoxyquinoline-3-carboxylate iscommercially available or synthetically accessible from ethyl4-hydroxy-7-methoxyquinoline-3-carboxylate (III) in two steps.Chlorination of compound (III) under conditions known to one skilled inthe art, for example, but not limited to, oxalyl chloride, thionylchloride, or phosphorus oxychloride, with or without a catalytic amountof DMF, in the presence or absence of a solvent such as DCM or CHCl₃, attemperatures ranging from 50° C. to about 70° C., for a period rangingfrom 2 to 4 h, preferably 2.5 h, provides ethyl4-chloro-7-methoxyquinoline-3-carboxylate. Subsequent reduction of ethyl4-chloro-7-methoxyquinoline-3-carboxylate, employing Pd/C underhydrogenation conditions, in a solvent such as MeOH or EtOH, in thepresence or absence of an acid such as acetic or formic acid, providesethyl 7-methoxyquinoline-3-carboxylate (IV). Commercially available orsynthetically accessible ethyl 7-methoxyquinoline-3-carboxylate (IV) isreacted under demethylation conditions, for example, HBr in H₂O or HOAc,at temperatures ranging from 80° C. to about 110° C., preferably 105° C.for a period of 0.5 h to 24 h, preferably about 2 h, to provide7-hydroxyquinoline-3-carboxylic acid. Ethyl7-hydroxyquinoline-3-carboxylate (V), where R³ is H, is obtained byesterification of 7-hydroxyquinoline-3-carboxylic acid, employingmethods known to one skilled in the art, for example, but not limitedto, reaction of 7-hydroxyquinoline-3-carboxylic acid with an acid suchas H₂SO₄, and the like, in a solvent such as EtOH, at temperaturesranging from 60° C. to about 80° C., preferably 75° C. for a period ofabout 12 to 24 h, preferably 20 h.

Ethyl 7-hydroxy-2-methylquinoline-3-carboxylate (V), where R₃ is —CH₃,is obtained in two steps from commercially available or syntheticallyaccessible 7-methoxy-2-methylquinoline-3-carboxylic acid. Demethylationof 7-methoxy-2-methylquinoline-3-carboxylic acid, employing methodspreviously described, for example, HBr in H₂O, at temperatures rangingfrom 80° C. to about 100° C., preferably ° C. for a period of 0.5 h to24 h, preferably about 2 h provides7-hydroxy-2-methylquinoline-3-carboxylic acid. Subsequent esterificationof 7-hydroxy-2-methylquinoline-3-carboxylic acid employing methodspreviously described, provides ethyl7-hydroxy-2-methylquinoline-3-carboxylate (V), where R₃ is —CH₃.

According to Scheme A, ethyl 2-(7-hydroxyquinolin-3-yl)acetate (VIII) isobtained in four steps from commercially available syntheticallyaccessible m-anisidine (II). m-Anisidine is treated with ethyl succinylchloride in a solvent such as THF, a suitably selected tertiary organicbase such as triethylamine (TEA), and the like, at a temperature between0° C. to about 65° C. and the reflux temperature of the solvent, toafford ethyl 4-((3-methoxyphenyl)amino)-4-oxobutanoate. Subsequentchlorination and cyclization of ethyl4-((3-methoxyphenyl)amino)-4-oxobutanoate with phosphoryl chloride andDMF, at temperatures ranging from 0° C. to about 80° C., preferably 0°C. for 20 minutes followed by 75° C. for 1.5 h, provides ethyl2-(2-chloro-7-methoxyquinolin-3-yl)acetate (VIa) and ethyl2-(2-chloro-5-methoxyquinolin-3-yl)acetate (VIb). Reduction of compounds(VIa) and (VIb) employing conditions known to one skilled in the art,for example Pd/C under hydrogenation conditions, in a solvent such asMeOH or EtOH, provides ethyl 2-(7-methoxyquinolin-3-yl)acetate (VII).Demethylation of ethyl 2-(7-methoxyquinolin-3-yl)acetate (VII),employing conditions known to one skilled in the art, for example, HBrin H₂O or HOAc, at temperatures ranging from 95° C. to about 110° C.,preferably 105° C., for a period of about 48 to 96 h, preferably 96 h.Subsequent esterification of 7-hydroxy-2-quinoline-3-carboxylic acidemploying methods previously described provides ethyl2-(7-hydroxyquinolin-3-yl)acetate (VIII).

According to Scheme B, compound (XI) is obtained in two steps from7-hydroxy-3,4-dihydroquinolin-2(1H)-one (IX). Alkylation of7-hydroxy-3,4-dihydroquinolin-2(1H)-one (IX) with commercially availableor synthetically accessible substituted benzyl halides of formula (X),where Z is —Br, n is 1 or 2 and R¹ is a suitably substituted aryl orheteroaryl moiety, in the presence of a base such as Cs₂CO₃, K₂CO₃,Na₂CO₃, NaH, DBU, and the like, in a polar aprotic solvent such as DMF,DMA, THF, ACN, DMSO, or a mixture thereof, at a temperature of about 25°C. to 75° C., preferably 25° C., for a period of 5 h providessubstituted 3,4-dihydroquinolin-2(1H)-ones. In a preferred embodiment,the base is Cs₂CO₃ and the solvent is ACN. The variable “PG” refers to asuitable nitrogen protecting group, for example, tert-butylcarbamoyl(BOC), benzyl, or substituted benzyl. Subsequent protection with a —BOCgroup, under conditions known to one skilled in the art, for example, byreaction with di-tert-butyl dicarbonate (BOC₂O), triethylamine, DMAP, ina solvent such as DCM provides compounds of formula (XI). Alkylation ofcompounds of formula (XI), by reaction with a base such as lithiumbis(trimethylsilyl)amide (LiHMDS), and the like, in a solvent such asTHF, and the like, ethyl bromoacetate, at temperatures ranging from −78°C. to 25° C., for a period of 16 to 24 h. In a separate step, subsequentdeprotection of the —BOC protecting group, under conditions known to oneskilled in the art, for example, removal using HCl, TFA, orp-toluenesulfonic acid, in a solvent such as MeOH, dioxane, or DCM,provides compounds of formula (XII). Substituted quinolin-2(1H)-ones areobtained from 3,4-dihydroquinolin-2(1H)-ones of formula (XII), underoxidation conditions, for example, by reaction with2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ), in a solvent such aschloroform, and the like, at ambient temperature for a period of about 3h. Substituted chloroquinoline compounds of formula (XIII) are preparedfrom substituted quinolin-2(1H)-ones, under conditions previouslydescribed, for example, reaction with a chlorinating agent such asoxalyl chloride, sulfonyl chloride or phosphorus oxychloride, in thepresence or absence of a catalytic amount of DMF, at temperaturesranging from 50° C. to about 70° C., for a period of about 1 hour.Compounds of Formula (I), where R¹ is a suitably substituted aryl orheteroaryl moiety, R² is —CH₂CO₂Et, and R³ is —H, is obtained byreacting a compound of formula (XIII) with a palladium catalyst such as[1′1′-bis(diphenylphosphino)ferrocene]palladium(11) dichloridedichloromethane adduct, in a solvent such as THF, and the like,N1,N1,N2,N2-tetramethylethane-1,2-diamine, sodium tetrahydroborate, at25° C., for a period of 24 to 48 h.

According to Scheme C, commercially available or syntheticallyaccessible 1,5-naphthyridine (XIV) is treated with a brominating agent,such as, but not limited to, Br₂, in the presence of sodium acetate, ina solvent such as, but not limited to, acetic acid, at temperaturesranging from 23° C. to 60° C., preferably 60° C. for a period of about24 h, preferably about 22 h, to provide 3,7-dibromo-1,5-naphthyridine.3-(Benzyloxy)-7-bromo-1,5-naphthyridine (XV), is obtained by reacting3,7-dibromo-1,5-naphthyridine, with sodium benzoxide, or a mixture ofbenzyl alcohol in the presence of a base such as Cs₂CO₃, K₂CO₃, DBU orNaH, in a solvent such as DMF, ACN, DMSO, xylenes or a mixture thereof,at temperatures ranging from 0° C. to 140° C. Palladium-catalyzedcarbonylation of 3-(benzyloxy)-7-bromo-1,5-naphthyridine (XV), employingmethods known to one skilled in the art, for example, reacting3-(benzyloxy)-7-bromo-1,5-naphthyridine with a palladium catalyst suchas Pd₂(dba)₃, (Pd(allyl)₂Cl₂)₂, and the like, in a solvent such astoluene or xylenes, in an atmosphere of carbon monoxide provides ethyl7-(benzyloxy)-1,5-naphthyridine-3-carboxylate. Removal of the benzylprotecting group under conditions known to one skilled in the art, forexample, by catalytic hydrogenation conditions including a catalyst suchas Pd black or Pd/C, a hydrogen source such as cyclohexadiene, ammoniumformate, or gaseous H₂, in a solvent such as MeOH, EtOH, or EtOAc,provides ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (XVI).Preferably, hydrogenation is performed using Pd/C and gaseous H₂ in asolvent such as MeOH or EtOH.

Compounds of formula (XVIII), are obtained by reacting substitutedbenzyl alcohols of formula (XVII), where R¹ is a suitably substitutedaryl or heteroaryl moiety, with 3,7-dibromo-1,5-naphthyridine, in thepresence of a base such as Cs₂CO₃, K₂CO₃, Na₂CO₃, NaH, or a mixturethereof, in a solvent such as NMP, DMA, DMF, DMSO or a mixture thereof,at temperatures ranging from 0° C. to 100° C., for a period of 3 to 24h. Compounds of Formula (I), where Y is N, R² is CH₂CO₂Et, and R³ is H,are obtained by palladium-catalyzed alkylation of intermediates offormula (XVIII). Alkylation reactions are performed in the presence of apalladium catalyst such as Pd₂(dba)₃, (Pd(allyl)₂Cl₂)₂, Pd(dba)₂,Pd(OAc)₂, and the like, a ligand such as t-Bu₃P, [(t-Bu)₃PH]BF₄, BINAP,and the like, and a base such as K₃PO₄, sodium tert-butoxide, Cs₂CO₃,LHMDS, NaOH, KOH, 4-DMAP, and the like, in a solvent such as DME,diethylmalonate, DMA, NMP, toluene, xylenes, DMF, or a mixture thereof,at a temperature from about 100° C. to about 140° C. Preferably,reactions are performed using Pd₂(dba)₃, [(t-Bu)₃PH]BF₄, and K₃PO₄, and18-crown-6, in diethylmalonate, at a temperature of about 115° C. for 24to 48 h; or (Pd(allyl)₂Cl₂)₂, BINAP, 4-DMAP, and potassium ethylmalonate, in xylenes, at 120° C. to 24 to 48 h.

Compounds of Formula (I), where Y is CH, R² is —CO₂Et or —CH₂CO₂Et, andR³ is —H or —CH₃, are prepared according to Scheme D, by the reaction ofcompounds of formula (V) or (VIII) with commercially available orsynthetically accessible substituted benzyl halide of formula (X), whereZ is —Cl or —Br, n is 1 or 2, and R¹ is a suitably substituted aryl orheteroaryl moiety, in the presence of a base such as Cs₂CO₃, K₂CO₃,Na₂CO₃, NaH, LHMDS, and the like, in a polar aprotic solvent such asDMF, DMA, THF, NMP, DMSO, or a mixture thereof, at a temperature ofabout 25° C. for a period of 3 h. In a preferred embodiment, the base isCs₂CO₃ and the solvent is DMF. Compounds of Formula (I), where Y is N,R³ is —H, and R² is CO₂Et, are prepared according to Scheme D, by thereaction of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate (XVI) withcommercially available or synthetically accessible substituted benzylchlorides of formula (X), where n is 1 or 2 and R¹ is a suitablysubstituted aryl or heteroaryl moiety, in the presence of a base such asCs₂CO₃, K₂CO₃, Na₂CO₃, NaH, and the like, in a polar aprotic solventsuch as DMF, DMA, THF, or a mixture thereof, at a temperature of about0° C. to 140° C. for a period of 2 to 24 h. In a preferred embodiment,the base is Cs₂CO₃ and the solvent is DMF. Transesterification ofcompounds of Formula (I), where Y is CH, R² is —CO₂Et or CH₂CO₂Et, underconditions known to one skilled in the art, for example, employing abase such as K₂CO₃, in a solvent such as MeOH, at ambient temperature,for about 8 to 24 h, provides compounds of Formula (I) where Y is CH,and R² is —CO₂CH₃ or CH₂CO₂CH₃. Transesterification can be conductedunder acidic or basic conditions.

Dialkyl-esters of Formula (I), where Y is CH, and R² is —C(CH₃)₂CO₂Etare prepared by the reaction of esters of Formula (I) where Y is CH orN, and R² is —CH₂CO₂Et, with a base such as KHMDS, LiHMDS, and the like,an alkylating agent such as methyl iodide, and the like, in a solventsuch as THF, dioxane, and the like, at a temperature of about 0° C. toambient temperature for about 0.25 to 2 h. Dialkyl-amides of Formula(I), where Y is CH, and R² is —C(CH₃)₂CONH₂, are prepared from thesaponification of esters of Formula (I), where Y is CH, and R² is—C(CH₃)₂CO₂Et employing conditions known to one skilled in the art.Subsequent chlorination employing methods previously described providesacid chlorides of Formula (I), where Y is CH, and R² is —C(CH₃)₂COCl,followed by amide formation, employing ammonium hydroxide, in a solventsuch as THF, at ambient temperature, for about 8 to 24 h, providescompounds of Formula (I), where Y is CH, and R² is —C(CH₃)₂CONH₂.

Amides of Formula (I), where Y is CH or N, and R² is —CH₂CONH₂, —CONH₂,are prepared employing methods known to one skilled in the art, forexample, reacting compounds of Formula (I) where Y is CH or N, and R² is—CH₂CO₂Et, —CO₂Et, with a suitable amine, such as ammonia, in a solventsuch as MeOH, and the like, at temperatures ranging from 0° C. to 40°C., for about 0.5 to 48 h. Alternatively, amides of Formula (I), where Yis CH, and R² is —CONH(alkyl) are prepared in three steps from estercompounds of Formula (I), where Y is CH, and R² is —CO₂Et.Saponification of ester compounds of Formula (I), where R² is —CO₂Et,under conditions known to one skilled in the art, for example byreaction with a base such as LiOH, and the like, in a solvent such asTHF, MeOH, or a mixture thereof, at a temperature of about 25° C., forabout 2 to 48 h, provide intermediate acid compounds, where R² is —CO₂H.Acid chloride intermediate compounds, where R² is —COCl, are preparedunder standard acid chloride formation conditions, for example, reactionof intermediate acid compounds, where R² is —CO₂H, with a chlorinatingagent such as oxalyl chloride, thionyl chloride, or phosphorusoxychloride, in the presence or absence of a catalytic amount of DMF, ina solvent such as DCM, THF, or a mixture thereof, at ambient temperaturefor about 0.5 to 2 h. Reaction of intermediate acid chloride compounds,where R² is —COCl, with primary amines, such as, methylamine, tert-butyl(2-aminoethyl)(methyl)carbamate, or tert-butyl (2-aminoethyl)carbamate,and the like, in a solvent such as DCM, and the like, provide amidecompounds of Formula (I), where Y is CH, and R² is —CONH(alkyl). In thecase where a —BOC group is employed, it may be removed using HCl, TFA orp-toluenesulfonic acid, in a solvent such as MeOH, dioxane, or DCM.Preferably, a —BOC group is removed with TFA in DCM.

Compound2-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamideis prepared from compounds of the formula (XII) with a suitable amine,such as ammonia, in a solvent such as MeOH, and the like, attemperatures ranging from 0° C. to 40° C., for about 0.5 to 48 h.Compound2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetamide isprepared from compounds of the formula (XII) after oxidation, andreaction with an amine as described above.

Alcohols of Formula (I), where Y is CH or N, and R² is —CH₂CH₂OH,—C(CH₃)₂CH₂OH, or —CH₂OH are prepared employing methods known to oneskilled in the art, for example, reacting compounds of Formula (I) whereY is CH or N, and R² is —CH₂CO₂Et, C(CH₃)₂CO₂Et, or —CO₂Et, with areducing agent such as LAH, NaBH₄, and the like, in a solvent such asTHF, diethyl ether, diglyme, and the like, at temperatures ranging from−78° C. to 80° C., for about 0.5 to 6 h.

Dialkyl-alcohols of Formula (I), where Y is CH or N, and R² is—CH₂C(CH₃)₂OH or —C(CH₃)₂OH are prepared by the reaction of esters ofFormula (I) where Y is CH or N, and R² is —CH₂CO₂Et or —CO₂Et, understandard Grignard conditions, with methylmagnesium bromide, in a solventsuch as THF, diethyl ether and the like, at a temperature of about 0°C., for about 0.25 to 2 h. Compounds of Formula (I), where Y is CH, andR² is —C(CH₃)₂OH are oxidized, under standard oxidation conditions, with3-chloroperoxybenzoic acid, in a solvent such as DCM, at temperatures ofabout 0° C. to room temperature, to provide N-oxide compounds of Formula(I).

Fluoro compounds of Formula (I), where Y is CH or N, and R² is —C(CH₃)₂Fare prepared by the reaction of alcohols of Formula (I), where Y is CHor N, and R² is —C(CH₃)₂OH, employing fluorinating conditions such, butnot limited to, reaction with XtalFluor®, triethylaminetrihydrofluoride, TEA, in a solvent such as DCM, and the like, at atemperature of about 0° C., for about 1 to 3 h.

Nitrile compounds of Formula (I), where Y is N, and R² is —CH₂CN, areprepared from alcohols of Formula (I), where Y is N, and R² is —CH₂OH intwo steps. Alcohols of Formula (I), where Y is N, and R² is —CH₂OH, aremesylated, under standard mesylation conditions, for example, byreaction with methanesulfonyl chloride, a base such as TEA, DIPEA, andthe like, in a solvent such as DCM, THF, and the like, at ambienttemperature, for about 2 to 24 h. Subsequent reaction of mesylatedcompounds of Formula (I) with sodium cyanide, in a solvent such as DMSO,at temperatures of 60° C. to 100° C., for about 2 to 48 h, providesnitrile compounds of Formula (I), where Y is N, and R² is —CH₂CN.

Amine compounds of Formula (I), where Y is CH, and R² is —CH₂NH₂, areprepared from alcohols of Formula (I), where Y is CH, and R² is —CH₂OHin two steps. Alcohols of Formula (I), where Y is CH, and R² is —CH₂OH,are mesylated, under standard mesylation conditions as previouslydescribed. Subsequent reaction of mesylated compounds of Formula (I)with ammonia, in a solvent such as MeOH, at temperatures of 80° C. to120° C., for about 1 to 6 h, provide amine compounds of Formula (I),where Y is CH, and R² is —CH₂NH₂.

Keto compounds of Formula (I), where Y is CH, and R² is —C(O)CH₃, areprepared from ester compounds of Formula (I), where Y is CH, and R² is—CO₂Et. Saponification of ester compounds of Formula (I) where Y is CH,and R² is —CO₂Et, under conditions known to one skilled in the art, forexample, employing sodium hydroxide, in a solvent such as MeOH, THF, ora mixture thereof, at ambient temperature, for about 1-4 h, providescarboxylate intermediates where R² is —CO₂H. Acid chloride intermediatecompounds, where R² is —COCl, are prepared as previously described, forexample, reaction of intermediate acid compounds, where R² is —CO₂H,with a chlorinating agent such as oxalyl chloride, with or without acatalytic amount of DMF, in a solvent such as DCM, THF, or a mixturethereof, at ambient temperature, for about 0.5 to 2 h. Followingstandard Weinreb ketone synthesis, acid chloride intermediates, where R²is —COCl are first converted to the Weinreb amide, where R² is—C(O)N(CH₃)OCH₃, under conditions known to one skilled in the art,followed by treatment with an organometallic reagent, such as methylmagnesium bromide, in a solvent such as THF, diethyl ether, or a mixturethereof, at a temperatures of about 0° C., for about 0.5 to 4 h, toprovide keto compounds of Formula (I), where Y is CH, and R² is—C(O)CH₃.

Alcohols of Formula (I), where Y is CH, and R² is —CH(OH)CH₃, areprepared by reducing keto compounds of Formula (I), where Y is CH, andR² is —C(O)CH₃, with a reducing agent such as sodium borohydride,lithium borohydride, or a mixture thereof, in a solvent such as THF,diethyl ether, and the like, at temperatures ranging from 0° C. toambient temperature. Enantiomerically pure alcohols of Formula (I),where Y is CH, and R² is —CH(OH)CH₃, are prepared by reducing ketocompounds of Formula (I), where Y is CH, and R² is —C(O)CH₃, with anorgano-boron catalyst such as (R) or (S) 2-methyl-CBS-oxazaborolidine, areducing agent such as borane, in a solvent such as toluene, THF, andthe like, at temperatures ranging from −20° C. to ambient temperature.

Ethers of Formula (I), where Y is CH, and R² is —CH₂OCH₃, are preparedemploying methods known to one skilled in the art, for example, byreacting compounds of Formula (I) where Y is CH, and R² is —CH₂OH, witha suitable base, such as sodium hydride, an alkylating agent such asmethyl iodide, in a solvent such as DMF, and the like, at temperaturesranging from 0° C. to 100° C.

Cycloalkyl compounds of Formula (I), where Y is CH or N, and R² isC₃₋₆cycloalkyl)OH, may be prepared from acid chlorides of compounds ofFormula (I), where Y is CH or N, and R² is —CO₂Cl. Acid chlorides ofFormula (I), prepared according to methods previously described, may betreated with ClCH₂I, MeLi and LiBr, and subsequently Li, as described inBarluenga et al., Synthesis, 1987, 6, 584-586, to provide cycloalkylcompounds of Formula (I), where Y is CH or N and R² is

Fluoro compounds of Formula (I), where Y is CH or N, and R² is —CF₂CO₂Etmay be prepared by the reaction of esters of Formula (I), where Y is CHor N, and R² is —CH₂CO₂Et, by reaction with a base such as lithiumbis(trimethylsilyl)amide, and the like, in a solvent such as THF, at atemperature of about −70° C., and a fluorinating agent such asn-fluorobis(phenylsulfonyl)amine, for about 1 to 3 h at a temperature ofabout 0° C.

Compounds of Formula (I) may be converted to their corresponding saltsusing methods known to those skilled in the art. For example, compoundsof Formula (I) may be treated with TFA, HCl, maleic acid, or citric acidin a solvent such as Et₂O, DCM, THF, or MeOH to provide thecorresponding salt forms.

Compounds prepared according to the schemes described above may beobtained as single enantiomers, diastereomers, or regioisomers, byenantio-, diastereo-, or regiospecific synthesis, or by resolution.Where compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Compounds prepared according to the schemes above may alternately beobtained as racemic (1:1) or non-racemic (not 1:1) mixtures of mixturesas diastereomers or regioisomers. Where racemic and non-racemic mixturesof enantiomers are obtained, single enantiomers may be isolated usingconventional separation methods known to one skilled in the art, such aschiral chromatography, recrystallization, diastereomeric salt formation,derivatization into diastereomeric adducts, biotransformation, orenzymatic transformation. Where regioisomeric or diastereomeric mixturesare obtained, single isomers may be separated using conventional methodssuch as chromatography or crystallization.

Protocols

In obtaining the compounds described in the examples below, and thecorresponding analytical data, the following experimental and analyticalprotocols were followed unless otherwise indicated.

Unless otherwise stated, reaction mixtures were magnetically stirred atroom temperature (rt) under nitrogen atmosphere. Where solutions were“dried”, they were generally dried over a drying agent such as Na₂SO₄ orMgSO₄. Where mixtures, solutions, and extracts were “concentrated”, theywere typically concentrated on a rotary evaporator under reducedpressure.

Reactions under microwave irradiation conditions were carried out in aCEM Discover-SP with Activent microwave reaction apparatus, model number909150, or Biotage Initiator, model number 355302.

Normal-phase flash column chromatography (FCC) was performed on silicagel (SiO₂) using packed or prepackaged cartridges, eluting with theindicated solvents.

LC/MS were obtained on a Waters 2695 Separations Unit, 2487 DualAbsorbance Detector, Micromass ZQ fitted with ESI Probe, or a WatersAcquity™ Ultra Performance LC (UPLC) Photodiode Array Detector (PDA).

Nuclear magnetic resonance (NMR) spectra were obtained in a Varian 400MHz or Bruker 400 MHz NMR. Samples were analyzed in either deuteratedchloroform (CDCl₃), methanol-d₄ (CD₃OD), or dimethyl sulfoxide-d₆(DMSO-d₆). For CDCl₃ samples, tetramethylsilane (TMS) was used as aninternal standard with the TMS resonance set to a chemical shift of 0.00ppm for ¹H NMR spectra. For CD₃OD the residual central resonance peak at3.31 for ¹H was used for chemical shift assignment and for DMSO-d₆ theresidual central resonance peak at 2.50 ppm for ¹H was used for chemicalshift assignment. The format of the ¹H NMR data below is: chemical shiftin ppm downfield the tetramethylsilane reference (multiplicity, couplingconstant J in Hz, integration).

Chemical names were generated using ChemDraw Ultra 12.0 (CambridgeSoftCorp., Cambridge, Mass.) or ChemAxon.

INTERMEDIATES Intermediate 1. Ethyl 7-hydroxyquinoline-3-carboxylate

Step A. Diethyl 2-(((3-methoxyphenyl)amino)methylene)malonate. Diethylethoxymethylenemalonate (5.00 g, 40.6 mmol) and m-anisidine (8.13 mL,40.6 mmol) were mixed and heated at 125° C. for 3 h. After cooling toambient temperature, residual solvent was removed under reduced pressureand dried under high vacuum to afford the title compound as a yellow oil(11.81 g, 99%). ¹H NMR (400 MHz, CDCl₃) δ 11.57 (d, J=13.7 Hz, 1H), 9.11(d, J=13.7 Hz, 1H), 7.90-7.83 (m, 1H), 7.31 (ddd, J=15.5, 8.2, 2.2 Hz,2H), 7.25 (d, J=2.3 Hz, 1H), 4.90 (q, J=7.0 Hz, 2H), 4.84 (q, J=7.3 Hz,2H), 4.42 (s, 3H), 1.98 (t, J=7.0 Hz, 3H), 1.92 (t, J=7.0 Hz, 3H).[M+H]=294.3.

Step B. Ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate. To a solutionof boiling Dowtherm™ (100 mL) was added diethyl2-(((3-methoxyphenyl)amino)methylene)malonate (20.0 g, 68.3 mmol). After15 minutes the reaction was cooled to ambient temperature and pouredinto hexanes (500 mL). The precipitate was collected by filtration anddried under high vacuum to yield the title compound as a brown solid(15.2 g, 90%). ¹H NMR (400 MHz, DMSO-d₆) δ 12.09 (d, J=5.9 Hz, 1H), 8.47(d, J=6.7 Hz, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.04-6.97 (m, 2H), 4.18 (q,J=7.0 Hz, 2H), 3.85 (s, 3H), 1.25 (t, J=7.2 Hz, 4H).

Step C. Ethyl 4-chloro-7-methoxyquinoline-3-carboxylate. To a solutionof ethyl 4-hydroxy-7-methoxyquinoline-3-carboxylate (2.72 g, 11.0 mmol)in chloroform (100 mL) was added oxalyl chloride (2.93 mL, 33.0 mmol)followed by 5 drops of DMF. The reaction was heated at 65° C. for 2.5 hbefore cooling to ambient temperature. The reaction mixture was pouredinto saturated NaHCO₃ (aq.) solution and the organics were extractedwith DCM. The combined organics were dried over MgSO₄, filtered andconcentrated under reduced pressure to afford the title compound as ayellow solid (2.69 g, 92%). ¹H NMR (400 MHz, CDCl₃) δ 9.20 (s, 1H), 8.33(d, J=9.4 Hz, 1H), 7.58 (br. s., 1H), 7.37 (d, J=9.0 Hz, 1H), 4.48 (q,J=6.8 Hz, 2H), 4.01 (s, 3H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=266.2.

Step D. Ethyl 7-methoxyquinoline-3-carboxylate. To a solution of ethyl4-chloro-7-methoxyquinoline-3-carboxylate (1.24 g, 4.67 mmol) in amixture of EtOAc (30 mL) and ethanol (30 mL) was added 10% Pd/C (10 mg).The flask was evacuated and filled with nitrogen three times andevacuated and filled with hydrogen three times and stirred overnight.After filtration through a plug of silica the reaction mixture wasconcentrated onto silica. Purification by FCC (SiO₂, 0-10% MeOH/DCM)afforded the title compound as a brown solid (955 mg, 89%). ¹H NMR (400MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 7.80 (d,J=9.0 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H), 4.45 (q,J=7.0 Hz, 2H), 4.01-3.93 (m, 3H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=232.2.

Step E. 7-Hydroxyquinoline-3-carboxylic acid. Ethyl7-methoxyquinoline-3-carboxylate (7.03 g, 30.4 mmol) was dissolved inHBr (48% aq., 150 mL) and was heated at 105° C. for 88.5 h. The reactionwas cooled to ambient temperature and the precipitate was collected byfiltration to afford the title compound as a brown solid (5.2 g, 90%).¹H NMR (400 MHz, DMSO-d₆) δ 12.05-11.67 (m, 1H), 9.49 (d, J=2.0 Hz, 1H),9.43 (s, 1H), 8.39 (d, J=9.8 Hz, 1H), 7.55-7.51 (m, 2H). [M+H]=190.2.

Step F. Ethyl 7-hydroxyquinoline-3-carboxylate. To a solution of7-hydroxyquinoline-3-carboxylic acid (273 mg, 1.44 mmol) in ethanol (6.0mL) was added H₂SO₄ (60 μL). The reaction was heated at 75° C.overnight. After cooling to ambient temperature the reaction wasconcentrated onto silica gel. Purification by FCC (SiO₂, 0-10% MeOH/DCM)afforded the title compound as a yellow solid (181 mg, 58%). ¹H NMR (400MHz, DMSO-d₆) δ 10.70 (s, 1H), 9.20 (d, J=2.3 Hz, 1H), 8.86 (d, J=2.0Hz, 1H), 8.08 (d, J=8.6 Hz, 1H), 7.33 (d, J=2.7 Hz, 1H), 7.28 (dd,J=9.0, 2.3, Hz, 1H), 4.41 (q, J=7.3 Hz, 2H), 1.39 (t, J=7.0 Hz, 3H).[M+H]=218.2.

Intermediate 2. Ethyl 2-(7-hydroxyquinolin-3-yl)acetate

Step A: Ethyl 4-((3-methoxyphenyl)amino)-4-oxobutanoate. To a solutionof m-anisidine (10 g, 81.3 mmol) in THF (240 mL) was added Et₃N (22 mL,217.8 mmol) followed by ethyl succinyl chloride (11.14 g, 67.9 mmol).The reaction mixture was stirred at ambient temperature for 15 minutes.The reaction was diluted with H₂O and EtOAc and the organic layer wasseparated. The organic layers were washed with H₂O, 10% HCl (aq), sat.NaHCO₃ (aq) and brine, dried over MgSO₄ and concentrated under reducedpressure to give the title compound as a pale yellow solid (17.5 g,86%). ¹H NMR (400 MHz, CDCl₃) δ 7.62-7.56 (m, 1H), 7.32-7.28 (m, 1H),7.19 (t, J=8.0 Hz, 1H), 6.95 (d, J=8.2 Hz, 1H), 6.65 (dd, J=8.2, 2.0 Hz,1H), 4.17 (d, J=7.0 Hz, 2H), 3.80 (s, 3H), 2.81-2.70 (m, 2H), 2.70-2.60(m, 2H), 1.26 (t, J=7.2 Hz, 3H). [M+H]=252.3.

Step B. Ethyl 2-(2-chloro-7-methoxyquinolin-3-yl)acetate and ethyl2-(2-chloro-5-methoxyquinolin-3-yl)acetate. DMF (8.0 mL, 95.9 mmol) wascooled to 0° C. and phosphoryl chloride (44 mL, 472 mmol) was slowlyadded and stirred at 0° C. for 5 minutes. Ethyl4-((3-methoxyphenyl)amino)-4-oxobutanoate (17.5 g, 69.7 mmol) was addedin one portion and stirred for 20 minutes at ambient temperature, thereaction was then heated at 75° C. for 1.5 h. The reaction mixture wasconcentrated under reduced pressure to yield a crude mixture of thetitle compounds as a brown oil. This was used directly in the next stepwith no further purification. [M+H]=280.19.

Step C. Ethyl 2-(7-methoxyquinolin-3-yl)acetate. To a solution of acrude mixture of ethyl 2-(2-chloro-7-methoxyquinolin-3-yl)acetate andethyl 2-(2-chloro-5-methoxyquinolin-3-yl)acetate in EtOAc (200 mL) andEtOH (200 mL) was added 10% Pd/C (50 mg, 0.47 mmol). The reactionmixture was placed under an atmosphere of hydrogen and stirred atambient temperature for 3 days. The crude reaction mixture was filteredthrough silica and concentrated to afford a brown oil. Purification byFCC (SiO₂, 0-5%, MeOH/DCM) yielded the title compound as a light brownsolid (6.0 g, 35% over 2 steps). ¹H NMR (400 MHz, CDCl₃) δ 8.76 (d,J=2.0 Hz, 1H), 8.00 (d, J=2.3 Hz, 1H), 7.67 (d, J=8.6 Hz, 1H), 7.41 (d,J=2.3 Hz, 1H), 7.20 (dd, J=9.0, 2.3 Hz, 1H), 4.18 (q, J=7.2 Hz, 2H),3.95 (s, 3H), 3.76 (s, 2H), 1.26 (t, J=6.8 Hz, 3H). [M+H]=246.2.

Step D. Ethyl 2-(7-hydroxyquinolin-3-yl)acetate. Ethyl2-(7-methoxyquinolin-3-yl)acetate (6 g, 24.5 mmol) was dissolved in HBr(48% aq., 40 mL) and heated at 105° C. for 4 days. The reaction mixturewas concentrated to a brown oil, which was dissolved in EtOH (50 mL) andH₂SO₄ (200 μL) was added. The reaction mixture was heated at 75° C. for2 h. The solution was concentrated under reduced pressure to an oil,which was quenched by the addition of saturated sodium carbonatesolution. The organics were extracted with DCM, combined and washed withbrine, and concentrated onto silica. Purification by FCC (SiO₂, 0-5%,MeOH/DCM) afforded the title compound as a light brown solid (2.19 g,39%). ¹H NMR (400 MHz, DMSO-d₆) δ 10.17 (s, 1H), 8.69 (d, J=2.0 Hz, 1H),8.11 (d, J=2.0 Hz, 1H), 7.82 (d, J=8.6 Hz, 1H), 7.27 (d, J=2.3 Hz, 1H),7.20 (dd, J=8.8, 2.5 Hz, 1H), 4.15 (q, J=7.0 Hz, 2H), 3.88 (s, 2H), 1.24(t, J=7.0 Hz, 3H). [M+H]=322.2.

Intermediate 3. 3,7-Dibromo-1,5-naphthyridine

1,5-Naphthyridine (30.80 g, 236.7 mmol) and sodium acetate (38.83 g,473.3 mmol) were dissolved in acetic acid (236.7 mL) and heated to 60°C. A solution of bromine (25.6 mL, 496.9 mmol) in acetic acid (35 mL)was added dropwise over 30 minutes. The solution was allowed to stir for22 h at 60° C. The reaction was cooled to ambient temperature thendiluted with water (250 mL) and basified with 4 N NaOH (aq.) (300 mL),where upon addition of base, a beige precipitate formed. The precipitatewas collected by filtration then washed with water, MeOH, and acetone.The remaining solid (54.7 g) was recrystallized from chloroform (1.36 L)to give the title compound as a pure, cream colored solid (30 g, 44%).¹H NMR (400 MHz, CDCl₃) δ 9.08-8.95 (m, 2H), 8.62 (dd, J=2.2, 0.7 Hz,1H), 8.46-8.35 (m, 1H), 8.23 (d, J=8.8 Hz, 1H), 7.79 (d, J=8.8 Hz, 1H),7.69 (dd, J=8.5, 4.3 Hz, 1H). [M+H]=286.9.

Intermediate 4. Ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate

Step A: 3-(Benzyloxy)-7-bromo-1,5-naphthyridine. To a solution of benzylalcohol (2.25 g, 20.8 mmol) in DMF (25 mL) was added NaH (60% in mineraloil, 0.83 g, 20.8 mmol). The resulting mixture was heated to 60° C. for10 minutes and was added to 3,7-dibromo-1,5-naphthyridine (Intermediate3, 5.0 g, 17.4 mmol) in DMF (25.0 mL) at 100° C. The resulting mixturewas stirred over night at 100° C., cooled, and concentrated underreduced pressure. Water (50 mL) was added and the aqueous layer waswashed with DCM (3×50 mL). The organic layers were combined, dried overNa₂SO₄, filtered and concentrated under reduced pressure. Purification(FCC, SiO₂, DCM/petroleum ether, 1:1) afforded the title compound as awhite solid (2.0 g, 36.7%).

Step B. Ethyl 7-(benzyloxy)-1,5-naphthyridine-3-carboxylate. A mixtureof 3-(benzyloxy)-7-bromo-1,5-naphthyridine (30.0 g, 95.5 mmol), Et₃N(19.47 g, 193 mmol), Pd(PhCN)₂Cl₂ (1.2 g, 3.13 mmol) and dppf (5.28 g,9.5 mmol) in EtOH (500 mL) was pressurized to 15 bars with CO gas. Thenthe mixture was heated at 140° C. for 24 h. After cooling to ambienttemperature, the solvent was removed under reduced pressure.Purification (FCC, SiO₂, DCM/EtOAc, 1:1) afforded the title compound asa yellow solid (14 g, 67%). [M+H]=309.3.

Step C: Ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate. The titlecompound was prepared in a manner analogous to Intermediate 2, Step C,substituting ethyl 7-(benzyloxy)-1,5-naphthyridine-3-carboxylate forethyl 2-(2-chloro-7-methoxyquinolin-3-yl)acetate. ¹H NMR (400 MHz,DMSO-d₆) δ 11.31 (br s, 1H), 9.28 (d, J=2.0 Hz, 1H), 8.90-8.61 (m, 2H),7.62 (d, J=2.0 Hz, 1H), 4.41 (q, J=7.1 Hz, 2H), 1.38 (t, J=7.2 Hz, 3H).[M+H]=219.2.

EXEMPLARY COMPOUNDS Example 1 Ethyl7-[(4-chlorophenyl)methoxy]quinoline-3-carboxylate

To a solution of ethyl 7-hydroxyquinoline-3-carboxylate (Intermediate 1,50 mg, 0.23 mmol) in DMF (1.15 mL) was added Cs₂CO₃ (150 mg, 0.46 mmol)and 4-chlorobenzyl chloride (41 mg, 0.25 mmol). The reaction was stirredovernight at ambient temperature. The reaction mixture was loadeddirectly onto a column and purification (FCC, SiO₂, EtOAc/hexanes,0-20%) afforded the title compound as a white solid (50 mg, 63%). ¹H NMR(400 MHz, CDCl₃) δ 9.37 (d, J=2.3 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 7.83(d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.45-7.35 (m, 4H), 7.34-7.29(m, 1H), 5.20 (s, 2H), 4.45 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.0 Hz, 3H).[M+H]=342.3.

Example 2 Ethyl 7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 4-fluorobenzyl chloride for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H), 7.82(d, J=9.0 Hz, 1H), 7.52 (d, J=2.3 Hz, 1H), 7.46 (dd, J=8.4, 5.7 Hz, 2H),7.31 (dd, J=9.0, 2.3, Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 5.19 (s, 2H),4.45 (q, J=7.0 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H). [M+H]=326.2.

Example 3 Ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-chlorobenzyl chloride for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.38 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H), 7.85(d, J=9.0 Hz, 1H), 7.51 (d, J=2.7 Hz, 2H), 7.40-7.29 (m, 4H), 5.22 (s,2H), 4.47 (q, J=7.3 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H). [M+H]=342.3.

Example 4 Ethyl 7-[(3-fluorophenyl)methoxy]quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-fluorobenzyl chloride for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.75 (d, J=1.6 Hz, 1H), 7.83(d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 1H), 7.43-7.20 (m, 4H), 7.07-6.99(m, 1H), 5.23 (s, 2H), 4.45 (q, J=7.3 Hz, 2H), 1.44 (t, J=7.2 Hz, 3H).[M+H]=326.3.

Example 5 Ethyl7-((3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-trifluoromethylbenzyl chloride for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.38 (d, J=2.0 Hz, 1H), 8.76 (d,J=1.6 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.76 (s, 1H), 7.71-7.49 (m, 4H),7.36 (dd, J=9.0, 2.7 Hz, 1H), 5.28 (s, 2H), 4.47 (q, J=7.2 Hz, 2H), 1.45(t, J=7.2 Hz, 3H). [M+H]=376.3.

Example 6 Ethyl7-((4-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 4-trifluoromethylbenzyl chloride for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.38 (d, J=2.3 Hz, 1H), 8.76 (d,J=1.6 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.70-7.57 (m, 4H), 7.51 (d, J=2.3Hz, 1H), 7.35 (dd, J=9.0, 2.3 Hz, 1H), 5.30 (s, 2H), 4.46 (q, J=7.3 Hz,2H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=376.2.

Example 7 Ethyl 7-((3-methylbenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-methylbenzyl chloride for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.38 (d, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H), 7.83(d, J=9.0 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.36-7.28 (m, 4H), 7.17 (d,J=5.9 Hz, 1H), 5.20 (s, 2H), 4.46 (q, J=7.0 Hz, 2H), 2.39 (s, 3H), 1.45(t, J=7.0 Hz, 3H). [M+H]=322.2.

Example 8 Ethyl 7-((4-methylbenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 4-methylbenzyl chloride for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H), 7.81(d, J=9.0 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.38 (d, J=8.2 Hz, 2H), 7.32(dd, J=8.8, 2.5 Hz, 1H), 7.22 (d, J=7.8 Hz, 2H), 5.19 (s, 2H), 4.46 (q,J=7.2 Hz, 2H), 2.37 (s, 3H), 1.45 (t, J=7.2 Hz, 3H). [M+H]=322.2.

Example 9 Ethyl 7-((3-methoxybenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-methoxybenzyl chloride for 4-chlorobenzyl chloride. ¹HNMR (400 MHz, CDCl₃) δ 9.38 (d, J=2.3 Hz, 1H), 8.75 (d, J=2.0 Hz, 1H),7.83 (d, J=9.0 Hz, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.38-7.30 (m, 2H),7.10-7.00 (m, 2H), 6.95-6.87 (m, 1H), 5.22 (s, 2H), 4.47 (q, J=7.3 Hz,2H), 3.83 (s, 3H), 1.46 (t, J=7.2 Hz, 3H). [M+H]=338.2.

Example 10 Ethyl 7-((4-methoxybenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 4-methoxybenzyl chloride for 4-chlorobenzyl chloride. ¹HNMR (400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.74 (d, J=2.0 Hz, 1H),7.81 (d, J=9.0 Hz, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.42 (d, J=8.6 Hz, 2H),7.33-7.27 (m, 1H), 6.96-6.92 (m, 2H), 5.16 (s, 2H), 4.46 (q, J=7.0 Hz,2H), 3.82 (s, 3H), 1.45 (t, J=7.2 Hz, 3H). [M+H]=338.4.

Example 11 Ethyl 7-((4-nitrobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 4-nitrobenzyl bromide for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.41-9.35 (m, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.28 (d,J=7.8 Hz, 2H), 7.87 (d, J=9.0 Hz, 1H), 7.67 (d, J=8.2 Hz, 2H), 7.49 (d,J=2.0 Hz, 1H), 7.37 (dd, J=9.0, 2.3 Hz, 1H), 5.35 (s, 2H), 4.51-4.41 (m,2H), 1.45 (dt, J=7.1, 1.0 Hz, 3H). [M+H]=353.3.

Example 12 Ethyl7-((4-fluoro-3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 4-fluoro-3-trifluorobenzyl chloride for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.39 (d, J=2.3 Hz, 1H), 8.77 (d,J=2.0 Hz, 1H), 7.87 (d, J=9.0 Hz, 1H), 7.55 (s, 1H), 7.50 (d, J=2.3 Hz,1H), 7.44-7.29 (m, 3H), 5.28 (s, 2H), 4.47 (q, J=7.0 Hz, 2H), 1.46 (t,J=7.2 Hz, 3H). [M+H]=394.3.

Example 13 Ethyl7-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-trifluoro-5-fluorobenzyl bromide for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.39 (d, J=2.3 Hz, 1H), 8.77 (d,J=2.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.75 (d, J=6.7 Hz, 1H), 7.71-7.64(m, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.34 (dd, J=2.5, 8.8 Hz, 1H), 7.28-7.26(m, 1H), 5.23 (s, 2H), 4.47 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H).[M+H]=394.3.

Example 14 Ethyl 7-((3,4-difluorobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3,4-difluorobenzyl chloride for 4-chlorobenzyl chloride. ¹HNMR (400 MHz, CDCl₃) δ 9.38 (d, J=2.3 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H),7.85 (d, J=9.0 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.36-7.29 (m, 2H),7.23-7.17 (m, 2H), 5.18 (s, 2H), 4.46 (q, J=7.0 Hz, 2H), 1.45 (t, J=7.0Hz, 3H). [M+H]=344.3.

Example 15 Ethyl 7-((3,5-difluorobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3,5-difluorobenzyl chloride for 4-chlorobenzyl chloride. ¹HNMR (400 MHz, CDCl₃) δ 9.38 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.0 Hz, 1H),7.86 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.35 (dd, J=2.5, 8.8 Hz,1H), 7.04-6.97 (m, 2H), 6.79 (tt, J=2.3, 8.8 Hz, 1H), 5.22 (s, 2H), 4.47(q, J=7.0 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H). [M+H]=344.3.

Example 16 Ethyl 7-((3,4,5-trifluorobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3,4,5-trifluorobenzyl chloride for 4-chlorobenzyl chloride.¹H NMR (400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.75 (d, J=1.2 Hz,1H), 7.84 (d, J=9.0 Hz, 1H), 7.44 (d, J=2.3 Hz, 1H), 7.31 (dd, J=2.3,9.0 Hz, 1H), 7.11 (t, J=7.0 Hz, 2H), 5.15 (s, 2H), 4.45 (q, J=7.2 Hz,2H), 1.47-1.39 (m, 3H). [M+H]=362.2.

Example 17 Ethyl 7-((3-chloro-4-fluorobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-chloro-4-fluorobenzyl bromide for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.38 (d, J=2.0 Hz, 1H), 8.76 (d,J=2.3 Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.56 (dd, J=2.0, 7.0 Hz, 1H),7.50 (d, J=2.3 Hz, 1H), 7.39-7.30 (m, 2H), 7.18 (t, J=8.6 Hz, 1H), 5.18(s, 2H), 4.47 (q, J=7.0 Hz, 2H), 1.46 (t, J=7.2 Hz, 3H). [M+H]=360.2.

Example 18 Ethyl 7-((3-nitrobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-nitrobenzyl chloride for 4-chlorobenzyl chloride. ¹H NMR(400 MHz, CDCl₃) δ 9.39 (d, J=2.0 Hz, 1H), 8.77 (d, J=2.0 Hz, 1H), 8.39(s, 1H), 8.23 (dd, J=1.6, 8.2 Hz, 1H), 7.88 (d, J=9.0 Hz, 1H), 7.85-7.80(m, 1H), 7.61 (t, J=8.0 Hz, 1H), 7.51 (d, J=2.3 Hz, 1H), 7.38 (dd,J=2.7, 9.0 Hz, 1H), 5.34 (s, 2H), 4.47 (q, J=7.2 Hz, 2H), 1.46 (t, J=7.0Hz, 3H). [M+H]=353.3.

Example 19 Ethyl 7-((3-chloro-5-fluorobenzyl)oxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 5-chloro-3-fluorobenzyl chloride for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.41-9.34 (m, 1H), 8.76 (d, J=2.0Hz, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.3 Hz, 1H), 7.34 (dd,J=2.7, 9.0 Hz, 1H), 7.27 (s, 1H), 7.13-7.03 (m, 2H), 5.20 (s, 2H), 4.46(q, J=7.0 Hz, 2H), 1.45 (t, J=7.2 Hz, 3H). [M+H]=360.2.

Example 20 Ethyl 7-((3-chlorobenzyl)oxy)-2-methylquinoline-3-carboxylate

Step A: 7-Hydroxy-2-methylquinoline-3-carboxylic acid.7-Methoxy-2-methylquinoline-3-carboxylic acid (100 mg, 0.46 mmol) wassuspended in HBr (aq.) (48%, 5 ml) and heated at 105° C. overnight. Thereaction was cooled to ambient temperature. The precipitate wascollected by filtration and dried under high vacuum to afford the titlecompound as a yellow solid (86 mg, 91%).

Step B: Ethyl 7-hydroxy-2-methylquinoline-3-carboxylate.7-Hydroxy-2-methylquinoline-3-carboxylic acid (860 mg, 4.24 mmol) wasdissolved in EtOH (29 mL) and H₂SO₄ (0.3 mL) was added. The reaction washeated at 75° C. for 23 h before being concentrated onto silica.Purification (FCC, SiO₂, 0-5%, MeOH/DCM) afforded the title compound asa yellow solid sulfate salt (1.128 g, 81%).

Step C: To a solution of ethyl 7-hydroxy-2-methylquinoline-3-carboxylate(100 mg, 0.43 mmol) in DMF (3.0 mL) was added Cs₂CO₃ (212 mg, 0.65 mmol)and 3-chlorobenzyl chloride (0.052 mL, 0.43 mmol). The reaction wasstirred overnight at ambient temperature. The reaction mixture wasloaded directly onto a column and purification (FCC, SiO₂, 0-40%,EtOAc/hexanes) afforded the title compound as a white solid (86 mg,59%). ¹H NMR (400 MHz, CDCl₃) δ 8.68 (s, 1H), 7.77 (d, J=8.6 Hz, 1H),7.48 (s, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.37-7.30 (m, 3H), 7.29-7.26 (m,1H), 5.19 (s, 2H), 4.42 (q, J=7.0 Hz, 2H), 2.97 (s, 3H), 1.44 (t, J=7.2Hz, 3H). [M+H]=356.3.

Example 21 Ethyl 7-((3-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 20,substituting 3-fluorobenzyl chloride for 3-chlorobenzyl chloride in StepC. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 7.76 (d, J=9.0 Hz, 1H),7.42-7.38 (m, 1H), 7.38-7.33 (m, 1H), 7.25-7.15 (m, 3H), 7.03 (dt,J=2.5, 8.5 Hz, 1H), 5.20 (s, 2H), 4.49-4.32 (m, 2H), 2.96 (s, 3H),1.49-1.35 (m, 3H). [M+H]=340.2.

Example 22 Ethyl 7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 20,substituting 4-fluorobenzyl chloride for 3-chlorobenzyl chloride in StepC. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 7.75 (d, J=9.0 Hz, 1H),7.50-7.38 (m, 3H), 7.22 (d, J=2.7 Hz, 1H), 7.09 (t, J=8.8 Hz, 2H), 5.16(s, 2H), 4.46-4.37 (m, 2H), 2.96 (s, 3H), 1.47-1.36 (m, 3H).[M+H]=340.3.

Example 23 Ethyl7-((3-chloro-4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 20,substituting 3-chloro-4-fluorochlorobenzyl chloride for 3-chlorobenzylchloride in Step C. ¹H NMR (400 MHz, CDCl₃) δ 8.67 (s, 1H), 7.79-7.74(m, 1H), 7.53 (dd, J=2.0, 7.0 Hz, 1H), 7.39 (s, 1H), 7.33 (ddd, J=2.0,4.2, 8.3 Hz, 1H), 7.24-7.21 (m, 1H), 7.19-7.13 (m, 1H), 5.14 (s, 2H),4.48-4.37 (m, 2H), 2.99-2.92 (m, 3H), 1.48-1.42 (m, 3H). [M+H]=374.2.

Example 24 Ethyl 7-(3-fluorophenethoxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 2-(3-fluorophenyl)ethyl bromide for 4-chlorobenzylchloride. ¹H NMR (400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.74 (d,J=2.0 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.33-7.26(m, 2H), 7.09 (d, J=7.4 Hz, 1H), 7.04 (td, J=2.0, 9.8 Hz, 1H), 6.95 (dt,J=2.2, 8.3 Hz, 1H), 4.46 (q, J=7.2 Hz, 2H), 4.37 (t, J=6.7 Hz, 2H), 3.18(t, J=6.7 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=340.3.

Example 25 Ethyl 7-(3-chlorophenethoxy)quinoline-3-carboxylate

The title compound was prepared in a manner analogous to Example 1,substituting 3-chlorophenyl ethyl bromide for 4-chlorobenzyl chloride.¹H NMR (400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.75 (d, J=2.0 Hz,1H), 7.81 (d, J=9.0 Hz, 1H), 7.46 (d, J=2.3 Hz, 1H), 7.32 (s, 1H),7.26-7.17 (m, 4H), 4.46 (q, J=7.2 Hz, 2H), 4.37 (t, J=6.7 Hz, 2H), 3.16(t, J=6.7 Hz, 2H), 1.45 (t, J=7.0 Hz, 3H). [M+H]=356.30.

Example 26 Methyl 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylate

To a solution of ethyl7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 20 mg,0.06 mmol) in MeOH (1 mL) and THF (1 mL) was added K₂CO₃. The reactionwas stirred overnight at ambient temperature. The crude reaction mixturewas concentrated onto silica and purification (FCC, SiO₂, 0-40%,EtOAc/hexanes) afforded the title compound as a white solid (12 mg,63%). ¹H NMR (400 MHz, CDCl₃) δ 9.37 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.3Hz, 1H), 7.84 (d, J=9.0 Hz, 1H), 7.50 (d, J=2.3 Hz, 2H), 7.38-7.30 (m,4H), 5.21 (s, 2H), 4.00 (s, 3H). [M+H]=328.2.

Example 27 2-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol

To a cooled solution, 0° C., of ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2, 140 mg,0.43 mmol) in THF (10.0 mL) was added methyl magnesium bromide (3.0 M,2.5 mL, 7.53 mmol). The reaction was stirred for 15 minutes at 0° C.before being quenched with a sat. NH₄Cl (aq.) solution. The aqueouslayer was extracted with EtOAc. The organic layers were combined andconcentrated onto silica. Purification (FCC, SiO₂, 0-5%, MeOH/DCM)afforded the title compound as a yellow solid (84 mg, 63%). ¹H NMR (400MHz, CDCl₃) δ 8.98 (d, J=2.3 Hz, 1H), 8.17 (d, J=2.3 Hz, 1H), 7.72 (d,J=9.0 Hz, 1H), 7.52-7.44 (m, 3H), 7.29-7.26 (m, 1H), 7.09 (t, J=8.8 Hz,2H), 5.17 (s, 2H), 1.70 (s, 6H). [M+H]=312.3.

Example 28 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate(Example 3) for ethyl 7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate(Example 2). ¹H NMR (400 MHz, CDCl₃) δ 8.98 (d, J=2.3 Hz, 1H), 8.17 (d,J=2.3 Hz, 1H), 7.73 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.44 (d, J=2.3 Hz,1H), 7.33 (s, 4H), 5.18 (s, 2H). [M+H]=328.2.

Example 29 2-(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl 7-((3,5-difluorobenzyl)oxy)quinoline-3-carboxylate(Example 15) for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, DMSO-d₆) δ 9.00 (d, J=2.3 Hz, 1H), 8.29 (d, J=2.3 Hz, 1H),7.94 (d, J=9.0 Hz, 1H), 7.47 (d, J=2.7 Hz, 1H), 7.37 (dd, J=2.7, 9.0 Hz,1H), 7.33-7.22 (m, 3H), 5.34 (d, J=3.5 Hz, 3H), 1.57 (s, 6H).[M+H]=330.3.

Example 30 2-(7-((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl 7-((3,4,5-trifluorobenzyl)oxy)quinoline-3-carboxylate(Example 16) for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, DMSO-d₆) δ 8.95 (d, J=2.3 Hz, 1H), 8.24 (d, J=2.3 Hz, 1H),7.89 (d, J=9.0 Hz, 1H), 7.49 (dd, J=8.6, 7.0 Hz, 2H), 7.43 (d, J=2.7 Hz,1H), 7.31 (dd, J=9.0, 2.3 Hz, 1H), 5.25 (s, 2H), 1.52 (s, 6H).[M+H]=348.3.

Example 31 2-(7-((4-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol

To a solution of ethyl7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example 22, 65mg, 0.19 mmol) in THF was added methyl magnesium bromide (3 M in Et₂O,0.5 mL, 1.5 mmol). The reaction was stirred for 30 minutes before beingquenched with a sat. NH₄Cl (aq.) solution. The aqueous layer wasextracted with EtOAc. The organic layers were combined and concentratedonto silica. Purification (FCC, SiO₂, 0-5%, MeOH/DCM) afforded the titlecompound as a yellow solid (28 mg, 45%). ¹H NMR (400 MHz, CDCl₃) δ 8.10(s, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.44 (dd, J=5.5, 8.2 Hz, 2H), 7.37 (d,J=2.0 Hz, 1H), 7.18 (dd, J=2.3, 9.0 Hz, 1H), 7.07 (t, J=8.6 Hz, 2H),5.13 (s, 2H), 2.95 (s, 3H), 1.75 (s, 6H). [M+H]=326.3.

Example 32 2-(7-((3-Chlorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 31,substituting ethyl7-((3-chlorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example 20) forethyl 7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example22). ¹H NMR (400 MHz, CDCl₃) δ 8.10 (s, 1H), 7.65 (d, J=8.6 Hz, 1H),7.46 (s, 1H), 7.37-7.26 (m, 4H), 7.21-7.16 (m, 1H), 5.14 (s, 2H), 2.94(s, 3H), 1.74 (s, 6H). [M+H]=342.2.

Example 332-(7-((3-Chloro-4-fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 31,substituting ethyl7-((3-chloro-4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate(Example 23) for ethyl7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example 22). ¹HNMR (400 MHz, CDCl₃) δ 8.11 (s, 1H), 7.69-7.63 (m, 1H), 7.55-7.48 (m,1H), 7.38-7.29 (m, 2H), 7.21-7.08 (m, 2H), 5.11 (s, 2H), 2.97-2.93 (m,3H), 1.76-1.73 (m, 6H). [M+H]=360.2.

Example 34 2-(7-((3-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 31,substituting ethyl7-((3-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example 21) forethyl 7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate (Example22). ¹H NMR (400 MHz, CDCl₃) δ 8.12 (s, 1H), 7.68 (d, J=9.0 Hz, 1H),7.40-7.31 (m, 2H), 7.25-7.18 (m, 3H), 7.05-6.97 (m, 1H), 5.19 (s, 2H),2.96 (s, 3H), 1.76 (s, 6H). [M+H]=326.2.

Example 35 (7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanol

To a cooled solution, −78° C., under nitrogen, of ethyl7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3, 172 mg,0.50 mmol) in THF (8.0 mL) was added LiAlH₄ (2.4 M in THF, 2.0 mL, 4.8mmol). The reaction mixture was stirred for 7 h before being quenchedwith a 1 N NaOH (aq.) solution. The crude reaction mixture was filteredthrough CELITE® and the aqueous layer was extracted with EtOAc. Theorganic layers were combined and concentrated onto silica. Purification(FCC, SiO₂, 0-5%, MeOH/DCM) afforded the title compound as a yellowsolid (115 mg, 76%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (d, J=2.3 Hz, 1H),8.20 (d, J=1.2 Hz, 1H), 7.94 (d, J=9.0 Hz, 1H), 7.64 (s, 1H), 7.57-7.43(m, 4H), 7.37 (dd, J=2.7, 9.0 Hz, 1H), 5.43 (t, J=5.7 Hz, 1H), 5.34 (s,2H), 4.71 (d, J=5.5 Hz, 2H). [M+H]=300.2.

Example 36 (7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)methanol

The title compound was prepared in a manner analogous to Example 35,substituting ethyl 7-((3,4,5-trifluorobenzyl)oxy)quinoline-3-carboxylate(Example 15) for ethyl7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example 3). ¹H NMR(400 MHz, DMSO-d₆) δ 8.81 (d, J=2.3 Hz, 1H), 8.20 (s, 1H), 7.95 (d,J=9.0 Hz, 1H), 7.49 (d, J=2.7 Hz, 1H), 7.38 (dd, J=2.5, 8.8 Hz, 1H),7.33-7.23 (m, 3H), 5.43 (t, J=5.5 Hz, 1H), 5.35 (s, 2H), 4.70 (d, J=5.5Hz, 2H). [M+H]=302.3.

Example 37 (7-((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)methanol

The title compound was prepared in a manner analogous to Example 35,substituting ethyl7-[(3,4,5-trifluorophenyl)methoxy]quinoline-3-carboxylate (Example 16)for ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate (Example3). ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=2.3 Hz, 1H), 8.20 (s, 1H),7.94 (d, J=9.0 Hz, 1H), 7.58-7.53 (m, 2H), 7.50 (d, J=2.3 Hz, 1H), 7.37(dd, J=2.5, 8.8 Hz, 1H), 5.45-5.41 (m, 1H), 5.30 (s, 2H), 4.70 (d, J=5.9Hz, 2H). [M+H]=320.3.

Example 38 2-(7-(3-Fluorophenethoxy)quinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl 7-(3-fluorophenethoxy)quinoline-3-carboxylate(Example 24), for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 8.98 (d, J=2.3 Hz, 1H), 8.25 (s, 1H), 7.73 (d, J=9.0Hz, 1H), 7.51 (br. s., 1H), 7.32-7.26 (m, 1H), 7.25-7.20 (m, 1H), 7.09(d, J=7.4 Hz, 1H), 7.04 (d, J=9.8 Hz, 1H), 6.98-6.91 (m, 1H), 4.36 (t,J=6.7 Hz, 2H), 3.17 (t, J=6.7 Hz, 2H), 1.70 (s, 6H). [M+H]=326.1.

Example 39 2-(7-(3-Chlorophenethoxy)quinolin-3-yl)propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl 7-(3-chlorophenethoxy)quinoline-3-carboxylate(Example 25) for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 8.96 (d, J=2.3 Hz, 1H), 8.16 (d, J=1.6 Hz, 1H), 7.68(d, J=9.0 Hz, 1H), 7.40 (d, J=2.3 Hz, 1H), 7.33-7.30 (m, 1H), 7.25-7.15(m, 4H), 4.31 (t, J=6.7 Hz, 2H), 3.14 (t, J=6.7 Hz, 2H), 1.70-1.67 (m,6H). [M+H]=342.1.

Example 40 7-((3-Chlorobenzyl)oxy)-3-(methoxymethyl)quinoline

To a cooled solution of NaH (60% in mineral oil, 12 mg, 0.3 mmol) in DMF(0.5 mL) under an atmosphere of nitrogen, was added a solution of(7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example 35, 30 mg, 0.10mmol) in DMF (0.5 mL). The reaction was stirred for 10 minutes. Methyliodide (0.019 mL, 0.3 mmol) was added and the reaction was stirred foran additional 25 minutes at 0° C. before being quenched with a sat.NH₄Cl (aq.) solution. The aqueous layer was extracted with EtOAc. Theorganic layers were combined and concentrated onto silica. Purification(FCC, SiO₂, 0-60%, EtOAc/hexanes) afforded the title compound as a whitesolid (19 mg, 61%). ¹H NMR (400 MHz, CDCl₃) δ 8.81 (d, J=2.0 Hz, 1H),8.05 (d, J=1.6 Hz, 1H), 7.73 (d, J=8.6 Hz, 1H), 7.50 (s, 1H), 7.46 (d,J=2.7 Hz, 1H), 7.39-7.27 (m, 4H), 5.19 (s, 2H), 4.62 (s, 2H), 3.45 (s,3H). [M+H]=314.2.

Example 41 7-((4-Fluorobenzyl)oxy)-3-(2-fluoropropan-2-yl)quinoline

XtalFluor® (66.19 mg, 0.29 mmol) was transferred to a flask and putunder nitrogen, then DCM (2 mL) was added via syringe. The reaction wascooled to 0° C. in an ice bath then triethylamine trihydrofluoride(62.76 μl, 0.39 mmol) and triethylamine (26.7 μL, 0.19 mmol) were addedvia syringe. The reaction was stirred until all solids dissolvedcompletely then was cooled to −78° C. in a dry ice/acetone bath. Asolution of 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol (Example27, 60 mg, 0.19 mmol) in DCM (1 mL) was added via syringe then thereaction was warmed to 0° C. and allowed to stir for 1 hour. Uponcompletion, a solution of NaHCO₃ (sat aq.) and EtOAc was added. Thecombined organics were separated and washed with a 50% aq. bleachsolution. The combined organics were dried over Na₂SO₄, filtered, andconcentrated under reduced pressure. Purification (FCC, SiO₂, 0-25%,EtOAc/Hexanes), and a second purification with preparative HPLC(Shimadzu SCL-10 VP, ACN/H₂O, 25-90% (0.1% TFA)) afforded the titlecompound as a pure solid (18.2 mg, 22%). ¹H NMR (400 MHz, CDCl₃) δ 9.08(d, J=1.8 Hz, 1H), 8.19 (d, J=2.0 Hz, 1H), 7.77 (d, J=9.0 Hz, 1H), 7.53(dd, J=5.4, 8.4 Hz, 2H), 7.43 (d, J=9.0 Hz, 1H), 7.29 (s, 1H), 7.12 (t,J=8.7 Hz, 2H), 5.35 (s, 2H), 1.99-1.63 (m, 6H). [M+H]=314.1.

Example 42 1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanone

Step A. Sodium 7-((4-fluorobenzyl)oxy)quinoline-3-carboxylate. To asolution of ethyl 7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate(Example 2, 430 mg, 1.32 mmol) in MeOH (2 mL) and THF (2 mL) was addedNaOH (95 mg, 2.38 mmol) in H₂O (2.0 mL). The reaction was stirred for 15minutes at ambient temperature. The crude reaction mixture wasconcentrated under reduced pressure to afford the title compound as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 9.29 (d, J=2.0 Hz, 1H), 8.60(d, J=2.0 Hz, 1H), 7.96 (d, J=9.0 Hz, 1H), 7.63 (dd, J=5.5, 8.6 Hz, 2H),7.50 (d, J=2.7 Hz, 1H), 7.35-7.25 (m, 3H), 5.31 (s, 2H). [M+H]=298.2

Step B. 7-((4-fluorobenzyl)oxy)quinoline-3-carbonyl chloride. To asolution of sodium 7-((4-fluorobenzyl)oxy)quinoline-3-carboxylate (452mg, 1.41 mmol) in DCM (14 mL) was added oxalyl chloride (0.378 mL, 4.23mmol), followed by 1 drop of DMF. The reaction was stirred for 30minutes at ambient temperature. The crude mixture was concentrated toafford a crude solid and dried under high vacuum for 30 minutes and usedwithout further purification in the next step.

Step C.7-((4-Fluorobenzyl)oxy)-N-methoxy-N-methylquinoline-3-carboxamide. To asolution of 7-((4-fluorobenzyl)oxy)quinoline-3-carbonyl chloride in DCM(14 mL) was added N,O-dimethylhydroxylamine hydrochloride (207 mg, 2.12mmol) and DIPEA (0.739 mL, 4.23 mmol). The reaction was stirred for 15minutes at ambient temperature before being concentrated onto silica.Purification (FCC, SiO₂, 0-80%, EtOAc/hexanes) afforded the titlecompound as a white solid (324 mg, 67%). ¹H NMR (400 MHz, CDCl₃) δ 9.18(d, J=2.0 Hz, 1H), 8.54 (d, J=1.6 Hz, 1H), 7.81 (d, J=9.0 Hz, 1H), 7.52(d, J=2.0 Hz, 1H), 7.51-7.44 (m, 2H), 7.32 (dd, J=2.3, 9.0 Hz, 1H), 7.11(t, J=8.8 Hz, 2H), 5.21 (s, 2H), 3.59 (s, 3H), 3.45 (d, J=0.8 Hz, 3H).[M+H]=341.3.

Step D. 1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone. To a cooledsolution, 0° C., under an atmosphere of nitrogen, of7-((4-Fluorobenzyl)oxy)-N-methoxy-N-methylquinoline-3-carboxamide (224mg, 0.667 mmol) in THF was added methyl magnesium bromide (3.0 M inEt₂O, 0.466 mL, 1.40 mmol). The reaction was stirred for 1 hour at 0° C.before being quenched with a sat. NH₄Cl (aq.) solution. The aqueouslayer was extracted with EtOAc. The organic layers were combined, washedwith brine and concentrated under reduced pressure onto silica.Purification (FCC, SiO₂, 0-50%, EtOAc/hexanes) afforded the titlecompound as a white solid (145 mg, 75%). ¹H NMR (400 MHz, CDCl₃) δ 9.36(d, J=2.0 Hz, 1H), 8.64 (s, 1H), 7.85 (d, J=9.0 Hz, 1H), 7.54 (s, 1H),7.46 (dd, J=5.7, 8.4 Hz, 2H), 7.33 (dd, J=2.3, 9.0 Hz, 1H), 7.10 (t,J=8.6 Hz, 2H), 5.20 (s, 2H), 2.72 (s, 3H). [M+H]=296.3.

Example 43 1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol

To a cooled solution, 0° C., of1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 53 mg,0.18 mmol) in THF was added NaBH₄ (8 mg, 0.24 mmol). The reactionmixture was stirred for 1 hour. A further portion of NaBH₄ (20 mg, 0.59mmol) was added and stirred for 30 minutes at 0° C. LiBH₄ (50 mg, 2.30mmol) was added and the reaction was stirred for 15 minutes before beingquenched with sat. NH₄Cl (aq.) solution. The aqueous layer was extractedwith EtOAc. The combined organic layers were washed with brine andconcentrated under reduced pressure onto silica. Purification (FCC,SiO₂, 0-5%, MeOH/DCM) afforded the title compound as a white solid (20mg, 38%). ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, J=1.6 Hz, 1H), 8.10 (s,1H), 7.73 (d, J=9.0 Hz, 1H), 7.53-7.43 (m, 3H), 7.31-7.26 (m, 1H), 7.09(t, J=8.6 Hz, 2H), 5.17 (s, 2H), 5.12 (q, J=6.5 Hz, 1H), 1.62 (d, J=6.7Hz, 3H). [M+H]=298.3.

Example 44 (R)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol

To a cooled solution, −78° C., of1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 52 mg,0.176 mmol) in toluene was added (R)-(+)-2-methyl-CBS-oxazaborolidine(97 mg, 0.352 mmol) followed by BH₃.DMS (2 M in THF, 0.176 mL, 0.352mmol). The reaction was warmed to −20° C. and stirred for 3 h followedby treatment with MeOH. The resulting mixture was warmed to ambienttemperature and sat. NaHCO₃ (aq.) solution was added. The aqueous layerwas extracted with EtOAc and the combined organic fractions were washedwith brine and concentrated under reduced pressure onto silica.Purification (FCC, SiO₂, 0-5%, MeOH/DCM) afforded the title compound asa white solid (29 mg, 56%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J=2.3Hz, 1H), 8.20 (d, J=2.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.61 (dd,J=5.5, 8.6 Hz, 2H), 7.51 (d, J=2.3 Hz, 1H), 7.33 (dd, J=2.5, 8.8 Hz,1H), 7.28 (t, J=9.0 Hz, 2H), 5.44 (d, J=4.3 Hz, 1H), 5.29 (s, 2H),5.01-4.91 (m, 1H), 1.47 (d, J=6.7 Hz, 3H). [M+H]=298.2.

Example 45 (S)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol

To a cooled solution, −78° C., of1-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)ethanone (Example 42, 52 mg,0.176 mmol) in toluene was added (S)-(−)-2-methyl-CBS-oxazaborolidine(97 mg, 0.352 mmol) followed by BH₃.DMS (2 M in THF, 0.176 mL, 0.352mmol). The reaction was warmed to −20° C. and stirred for 3 h beforebeing quenched with MeOH. The reaction was warmed to ambient temperatureand sat. NaHCO₃ (aq.) solution was added. The aqueous layer wasextracted with EtOAc and the combined organic fractions were washed withbrine and concentrated under reduced pressure onto silica. Purification(FCC, SiO₂, 0-5%, MeOH/DCM) afforded the title compound as a white solid(9 mg, 17%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.85 (d, J=2.3 Hz, 1H), 8.20(d, J=2.0 Hz, 1H), 7.93 (d, J=9.0 Hz, 1H), 7.61 (dd, J=5.5, 8.6 Hz, 2H),7.51 (d, J=2.3 Hz, 1H), 7.33 (dd, J=2.5, 8.8 Hz, 1H), 7.28 (t, J=9.0 Hz,2H), 5.44 (d, J=4.3 Hz, 1H), 5.29 (s, 2H), 5.01-4.91 (m, 1H), 1.47 (d,J=6.7 Hz, 3H). [M+H]=298.2.

Example 46 7-((3-Chlorobenzyl)oxy)-N-methylquinoline-3-carboxamide

Step A: 7-((3-Chlorobenzyl)oxy)quinoline-3-carboxylic acid. To asolution of ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate(Example 3, 150 mg, 0.44 mmol) in MeOH (0.7 mL) and THF (1.7 mL) wasadded LiOH (13 mg, 0.54 mmol) in H₂O (1.7 mL). The reaction was stirredfor 14 h at ambient temperature. The crude reaction mixture wasconcentrated to dryness under reduced pressure. 10% HCl (aq.) (6.0 mL)was added, and the precipitate was collected and dried under highpressure to afford the title compound as a white solid (106 mg, 77%). ¹HNMR (400 MHz, DMSO-d₆) δ 9.25 (d, J=2.3 Hz, 1H), 8.79 (d, J=2.3 Hz, 1H),8.25 (s, 1H), 8.03 (d, J=9.4 Hz, 1H), 7.63 (s, 1H), 7.58-7.41 (m, 4H),5.37 (s, 2H). [M+H]=314.2.

Step B: 7-((3-Chlorobenzyl)oxy)-N-methylquinoline-3-carboxamide. To asolution of 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylic acid (50 mg,0.16 mmol) in DCM (1.5 mL) was added oxalyl chloride (0.042 mL, 0.48mmol) followed by 1 drop of DMF. After 30 minutes, methylamine (2M inTHF, 1 mL, 2 mmol) was added to the reaction. The reaction was stirredfor 14 h. The crude reaction was loaded directly onto a column andpurification (FCC, SiO₂, 0-10%, MeOH/DCM) afforded the title compound asa white solid (19 mg, 37%). ¹H NMR (400 MHz, CDCl₃) δ 9.17 (d, J=2.3 Hz,1H), 8.53 (d, J=2.0 Hz, 1H), 7.82 (d, J=9.0 Hz, 1H), 7.49 (d, J=2.7 Hz,2H), 7.38-7.31 (m, 4H), 6.28-6.22 (m, 1H), 5.21 (s, 2H), 3.10 (d, J=4.7Hz, 3H). [M+H]=327.2.

Example 47N-(2-Aminoethyl)-7-((3-chlorobenzyl)oxy)quinoline-3-carboxamide

Step A: 7-((3-chlorobenzyl)oxy)quinoline-3-carbonyl chloride. To asolution of 7-((3-chlorobenzyl)oxy)quinoline-3-carboxylic acid (Example46, product from Step A, 50 mg, 0.16 mmol) in DCM (1.5 mL) was addedoxalyl chloride (0.1 mL, 1.13 mmol), followed by 1 drop of DMF. After 30minutes the reaction was concentrated under reduced pressure to afford ayellow foam, and further dried under high vacuum for 15 minutes toafford the title compound, which was used without further purificationin the next step.

Step B: tert-Butyl(2-(7-((3-chlorobenzyl)oxy)quinoline-3-carboxamido)ethyl)carbamate. To asolution of 7-((3-chlorobenzyl)oxy)quinoline-3-carbonyl chloride in THF(1.5 mL) was added tert-butyl (2-aminoethyl)carbamate (38 mg, 0.23 mmol)and triethylamine (0.044 mL, 0.32 mmol). The reaction was stirred for 14h. The crude reaction was loaded directly onto a column and purification(FCC, SiO₂, 0-5%, MeOH/DCM) afforded the title compound as a white solid(44 mg, 60%). ¹H NMR (400 MHz, CDCl₃) δ 9.31-9.20 (m, 1H), 8.61-8.51 (m,1H), 7.80 (d, J=9.0 Hz, 1H), 7.68-7.60 (m, 1H), 7.49 (s, 2H), 7.40-7.29(m, 4H), 5.20 (s, 2H), 5.09-4.92 (m, 1H), 3.68-3.59 (m, 2H), 3.50-3.43(m, 2H), 1.44 (s, 9H). [M+H]=456.3

Step C: N-(2-Aminoethyl)-7-((3-chlorobenzyl)oxy)quinoline-3-carboxamide.To a cooled solution, 0° C., of tert-Butyl(2-(7-((3-chlorobenzyl)oxy)quinoline-3-carboxamido)ethyl)carbamate inDCM (1 mL) was added TFA (1 mL). The reaction was stirred for 1 hour,and concentrated under reduced pressure. The reaction mixture was takenup in MeOH and concentrated under reduced pressure to afford the titlecompound as a white solid, TFA salt (57 mg, 100%) ¹H NMR (400 MHz,DMSO-d₆) δ 9.22 (d, J=2.0 Hz, 1H), 8.88 (t, J=5.5 Hz, 1H), 8.76 (s, 1H),8.03 (d, J=9.0 Hz, 1H), 7.60 (s, 1H), 7.54 (d, J=2.3 Hz, 1H), 7.51-7.39(m, 4H), 5.34 (s, 2H), 3.55 (q, J=6.3 Hz, 2H), 3.10-2.95 (m, 2H).[M+H]=356.3

Example 487-((3-Chlorobenzyl)oxy)-N-(2-(methylamino)ethyl)quinoline-3-carboxamide

The title compound was prepared in a manner analogous to Example 47,substituting tert-butyl (2-aminoethyl)(methyl)carbamate for tert-butyl(2-aminoethyl)carbamate in Step B. ¹H NMR (400 MHz, DMSO-d₆) δ 9.23 (d,J=2.3 Hz, 1H), 8.96 (t, J=5.7 Hz, 1H), 8.78 (d, J=2.0 Hz, 1H), 8.04 (d,J=9.0 Hz, 1H), 7.60 (s, 1H), 7.55 (d, J=2.3 Hz, 1H), 7.51-7.38 (m, 4H),5.34 (s, 2H), 3.60 (q, J=5.7 Hz, 2H), 3.21-3.04 (m, 2H), 2.61 (t, J=5.3Hz, 3H). [M+H]=370.3.

Example 497-((3-Chlorobenzyl)oxy)-N-(2-(dimethylamino)ethyl)quinoline-3-carboxamide

The title compound was prepared in a manner analogous to Example 47,steps A-B, substituting N1,N1-dimethylethane-1,2-diamine for tert-butyl(2-aminoethyl)carbamate in Step B. ¹H NMR (400 MHz, DMSO-d₆) δ 9.33-9.25(m, 1H), 9.05-8.96 (m, 1H), 8.86-8.79 (m, 1H), 8.10-8.04 (m, 1H),7.67-7.64 (m, 1H), 7.60-7.58 (m, 1H), 7.57-7.45 (m, 4H), 5.39 (s, 2H),3.73-3.58 (m, 2H), 3.22-2.98 (m, 2H), 2.83-2.62 (m, 6H). [M+H]=384.3.

Example 50 (7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanamine

Step A. (7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methyl methanesulfonate.To a solution of (7-((3-chlorobenzyl)oxy)quinolin-3-yl)methanol (Example35, 55 mg, 0.18 mmol) in THF (1.8 mL) was added DIPEA (0.064 mL, 0.37mmol), followed by methanesulfonyl chloride (0.014 mL, 0.18 mmol). Thereaction was stirred at ambient temperature overnight. The crudereaction was loaded directly onto a column, purification (FCC, SiO₂,0-40%, EtOAc/hexanes) afforded the title compound as a white solid (44mg, 76%). ¹H NMR (400 MHz, CDCl₃) δ 8.85 (d, J=2.3 Hz, 1H), 8.10 (s,1H), 7.74 (d, J=9.0 Hz, 1H), 7.48 (d, J=9.4 Hz, 2H), 7.41-7.28 (m, 4H),5.20 (s, 2H), 4.76 (s, 2H). [M+H]=318.2

Step B. (7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanamine. A solution of7-((3-chlorobenzyl)oxy)quinolin-3-yl)methyl methanesulfonate (44 mg,0.14 mmol) in a 7 N solution of ammonia in MeOH was heated in themicrowave at 100° C. for one hour. The crude reaction mixture wasconcentrated under reduced pressure. DCM was added and the precipitatewas collected to afford the title compound as a pale yellow solid (24mg, 59%). ¹H NMR (400 MHz, DMSO-d₆) δ 8.95 (d, J=2.3 Hz, 1H), 8.41 (d,J=2.0 Hz, 1H), 7.97 (d, J=9.0 Hz, 1H), 7.64 (s, 1H), 7.57-7.42 (m, 5H),5.36 (s, 2H), 4.25 (s, 2H). [M+H]=299.2.

Example 51 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide

Procedure 1. The title compound was prepared in a manner analogous toExample 1, substituting 3-chlorobenzyl chloride for 4-chlorobenzylchloride and ethyl 2-(7-hydroxyquinolin-3-yl)acetate (Intermediate 2)for ethyl 7-hydroxyquinoline-3-carboxylate (Intermediate 1). ¹H NMR (400MHz, CDCl₃) δ 8.76 (d, J=2.3 Hz, 1H), 8.02 (s, 1H), 7.71 (d, J=9.0 Hz,1H), 7.52-7.43 (m, 2H), 7.32 (dd, J=12.7, 6.5 Hz, 4H), 5.19 (s, 2H),4.18 (q, J=7.0 Hz, 2H), 3.77 (s, 2H), 1.26 (t, J=7.0 Hz, 3H).[M+H]=356.2.

Procedure 2. Step A:7-((3-Chlorobenzyl)oxy)-3,4-dihydroquinolin-2(1H)-one. To a slurry of7-hydroxy-3,4-dihydroquinolin-2(1H)-one (32.4 g, 0.20 mol), and K₂CO₃(54.92 g, 0.40 mol) in ACN (162 mL) was added 3-chlorobenzyl bromide(26.1 mL, 0.20 mol). The reaction was heated to 60° C. for 18 h. Thereaction mixture was cooled and quenched into 650 mL of ice water andstirred for 20 min. The solid was filtered and dried to furnish a whitesolid (55.4 g, 97%), which was carried on without further purificationto the next step. ¹H NMR (400 MHz, CDCl₃) δ 8.78 (br s, 1H), 7.43 (s,1H), 7.31 (s, 3H), 7.06 (d, J=8.3 Hz, 1H), 6.58 (dd, J=8.3, 2.3 Hz, 1H),6.46 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 2.96-2.84 (m, 2H), 2.63 (t, J=7.5Hz, 2H). [M+H]=288.1.

Step B: tert-Butyl7-((3-chlorobenzyl)oxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate. Toa slurry of 7-((3-chlorobenzyl)oxy)-3,4-dihydroquinolin-2(1H)-one (30 g,0.09 mol) in DCM (153 mL) was added BOC anhydride (22.40 mL, 0.10 mol),triethylamine (12.35 mL, 0.09 mol) and 4-dimethylaminopyridine (0.11 g,0.90 mmol) at ambient temperature. The resulting slurry was stirred atambient temperature for 4 h. The reaction was quenched into water (150mL). The organic layer was separated and washed with 1N aq. HCl (100 mL)and sat. (aq.) ammonium chloride (100 mL) and dried over Na₂SO₄ andconcentrated under reduced pressure to a yellow oil that solidified uponstanding. The solid was triturated in hexanes (200 mL) to yield thedesired product (28.0 g, 81%), which was carried on without furtherpurification to the next step. ¹H NMR (400 MHz, CDCl₃) δ 7.41 (s, 1H),7.36-7.28 (m, 3H), 7.08 (d, J=8.3 Hz, 1H), 6.65 (dd, J=8.3, 2.3 Hz, 1H),6.59 (d, J=2.3 Hz, 1H), 5.02 (s, 2H), 2.95-2.81 (m, 2H), 2.65 (dd,J=8.4, 6.1 Hz, 2H), 1.60 (s, 9H). [M+H]=388.0.

Step C: tert-Butyl7-((3-chlorobenzyl)oxy)-3-(2-ethoxy-2-oxoethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate.To a solution of tert-butyl7-((3-chlorobenzyl)oxy)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate (34g, 0.09 mol) in THF (50.09 mL) was added a solution of lithiumbis(trimethylsilyl)amide (1.06 M in THF, 99.24 mL, 0.11 mol) at −78° C.The reaction was stirred at that temperature for 30 minutes after whichethyl bromoacetate (9.70 mL, 0.09 mol) was added. The reaction wasallowed to warm to ambient temperature, stirred overnight and quenchedinto water (250 mL). The aqueous layer was extracted with EtOAc (2×50mL) and the combined organic layers were washed with brine and driedover MgSO₄. The organics were concentrated under reduced pressure toafford a yellow-brown oil and carried on crude to the next step. ¹H NMR(400 MHz, CDCl₃) δ 7.35 (s, 1H), 7.27-7.22 (m, 3H), 7.02 (d, J=8.4 Hz,1H), 6.59 (dd, J=8.3, 2.5 Hz, 1H), 6.49 (d, J=2.4 Hz, 1H), 4.95 (s, 2H),4.12 (q, J=7.2 Hz, 2H), 3.06-2.91 (m, 1H), 2.87-2.70 (m, 2H), 2.60 (d,J=7.5 Hz, 1H), 2.37 (d, J=8.9 Hz, 1H), 1.54-1.44 (m, 9H), 1.26-1.19 (m,3H). [M+H]=374.2.

Step D: Ethyl2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate.To crude tert-butyl7-((3-chlorobenzyl)oxy)-3-(2-ethoxy-2-oxoethyl)-2-oxo-3,4-dihydroquinoline-1(2H)-carboxylate(115.7 g, 244.1 mmol) was added a 4.0 M 1,4-dioxane hydrochloridesolution (200 mL, 0.8 mol) in an ice bath. After addition, the ice bathwas removed and the reaction was warmed to ambient temperature. Thereaction was concentrated to a yellow oil and azeotroped with toluene(2×250 mL) to furnish a brown oil. The oil was diluted in toluene (400mL) followed by 2-propanol (400 mL). The resulting white ppt that wasformed was filtered and washed with 2-propanol to furnish the desiredproduct as a white solid. The mother liquor was concentrated to a brownsolid that was triturated with 2-propanol (400 mL), filtered and washedwith 2-propanol to furnish a second crop of product (38.3 g). The twocrops were combined to give (50.3 g, 55%) of the title compound. ¹H NMR(400 MHz, CDCl₃) δ 7.88 (s, 1H), 7.43 (s, 1H), 7.35-7.29 (m, 3H), 7.06(d, J=8.3 Hz, 1H), 6.59 (dd, J=8.3, 2.4 Hz, 1H), 6.39 (d, J=2.4 Hz, 1H),5.02 (s, 2H), 4.23-4.15 (m, 2H), 3.12-2.92 (m, 3H), 2.92-2.77 (m, 1H),2.48 (dd, J=16.2, 7.5 Hz, 1H), 1.29 (t, J=7.1 Hz, 3H). [M+H]=374.2.

Step E: Ethyl2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetate. To asolution of ethyl2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate(50.3 g, 134.5 mmol) in chloroform (905.2 mL) was added4,5-dichloro-3,6-dioxocyclohexa-1,4-diene-1,2-dicarbonitrile (36.65 g,161.4 mmol). The reaction was poured into 500 mL sat (aq) NaHCO₃ andstirred for 15 min. To the resulting slurry was added diatomaceous earth(CELITE®) and the mixture was filtered over CELITE®. The phases wereseparated and the subsequent CELITE® washes, chloroform (2×400 mL), wereused to extract the aqueous layer. The combined organic layers weredried over Na₂SO₄ and concentrated under reduced pressure to afford abrown/red solid. The solid was triturated in 2-propanol (700 mL) andfiltered to furnish the title compound (31.4 g, 55%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.73 (s, 1H), 11.91-11.57 (m, 1H), 7.77 (s, 1H), 7.55 (s,2H), 7.43 (t, J=4.8 Hz, 3H), 6.87 (s, 2H), 5.17 (s, 2H), 4.06 (d, J=7.0Hz, 2H), 3.48 (s, 2H), 1.17 (t, J=7.2 Hz, 3H). [M+H]=372.1.

Step F: Ethyl 2-(2-chloro-7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate.To a slurry of ethyl2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetate (31.4g, 0.08 mol) in chloroform (314 mL) at ambient temperature was addedoxalyl dichloride (21.7 mL, 0.25 mol) and DMF (0.66 mL, 0.01 mol). Theresulting slurry was heated to reflux for 1 h. The reaction was quenchedwith sat. aqueous NaHCO₃ (400 mL). The aqueous layer was extracted withDCM (2×200 mL) and the combined organic layers were washed with brineand dried over Na₂SO₄. The organic layer was concentrated under reducedpressure to furnish a black solid that was triturated in 1:1EtOAc:hexanes (400 mL) and filtered. The solid was recrystallized fromMeOH to furnish (17.0 g, 52%). Two additional crops of product wereacquired from the mother liquor to furnish a total of 27.8 g (84.3%) ofthe title compound. ¹H NMR (400 MHz, DMSO-d₆) δ 8.34 (s, 1H), 7.93 (d,J=9.0 Hz, 1H), 7.59 (s, 1H), 7.51-7.37 (m, 5H), 5.31 (s, 2H), 4.13 (q,J=7.1 Hz, 2H), 3.94 (s, 2H), 1.19 (t, J=7.1 Hz, 3H). [M+H]=390.2

Step G: Ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate. Asolution of ethyl2-(2-chloro-7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (5 g, 12.8mmol) in THF (50 mL) was degassed with nitrogen for 5 minutes and[1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complexwith dichloromethane (1.36 g, 1.67 mmol) was added, followed byN1,N1,N2,N2-tetramethylethane-1,2-diamine (3.84 mL, 25.6 mmol) andsodium tetrahydroborate (969 mg, 25.6 mmol). The resulting solution wasstirred at ambient temperature. After 4 h an additional portion of1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex withdichloromethane (50 mg, 0.06 mmol) and sodium tetrahydroborate (969 mg,25.6 mmol) were added and stirred overnight. The reaction was quenchedinto sat. aqueous NH₄Cl and extracted with EtOAc (3×30 mL). The combinedorganic layers were dried over MgSO₄ and concentrated under reducedpressure to afford a brown oil. Purification (FCC, SiO₂, 0-60%,EtOAc/hexanes) afforded the title compound as a colorless oil (2.5 g,55%) that crystallized upon standing. ¹H NMR (400 MHz, CDCl₃) 8.76 (d,J=2.3 Hz, 1H), 8.02 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.52-7.43 (m, 2H),7.32 (dd, J=6.5, 12.7 Hz, 4H), 5.19 (s, 2H), 4.18 (q, J=7.0 Hz, 2H),3.77 (s, 2H), 1.26 (t, J=7.0 Hz, 3H). [M+H]=356.2.

Example 52 Ethyl 2-(7-((3-fluorobenzyl)oxy)quinolin-3-yl)acetate

The title compound was prepared in a manner analogous to Example 1,substituting 3-fluorobenzyl chloride for 4-chlorobenzyl chloride andethyl 2-(7-hydroxyquinolin-3-yl)acetate (Intermediate 2) for ethyl7-hydroxyquinoline-3-carboxylate (Intermediate 1). ¹H NMR (400 MHz,CDCl₃) δ 8.76 (d, J=2.3 Hz, 1H), 8.01 (s, 1H), 7.71 (d, J=9.0 Hz, 1H),7.44 (d, J=2.3 Hz, 1H), 7.40-7.32 (m, 1H), 7.31-7.27 (m, 1H), 7.25-7.18(m, 2H), 7.07-6.98 (m, 1H), 5.21 (s, 2H), 4.18 (q, J=7.0 Hz, 2H), 3.77(s, 2H), 1.26 (t, J=7.0 Hz, 3H). [M+H]=340.3.

Example 53 Ethyl 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)acetate

The title compound was prepared in a manner analogous to Example 1,substituting 4-fluorobenzyl chloride for 4-chlorobenzyl chloride andethyl 2-(7-hydroxyquinolin-3-yl)acetate (Intermediate 2) for ethyl7-hydroxyquinoline-3-carboxylate (Intermediate 1). ¹H NMR (400 MHz,CDCl₃) δ 8.76 (d, J=2.0 Hz, 1H), 8.02 (s, 1H), 7.70 (d, J=9.0 Hz, 1H),7.51-7.41 (m, 3H), 7.28 (d, J=1.6 Hz, 1H), 7.09 (t, J=8.6 Hz, 2H), 5.17(s, 2H), 4.23-4.14 (m, 2H), 3.77 (s, 2H), 1.26 (dt, J=1.0, 7.1 Hz, 3H).[M+H]=340.3.

Example 54 Methyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate

To a solution of ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate(Example 51, 50 mg, 0.14 mmol) in MeOH (3.0 mL) was added K₂CO₃ (50 mg,0.36 mmol). The reaction was stirred at ambient temperature for 30minutes. The reaction was loaded directly onto the column andpurification (FCC, SiO₂, 0-50%, EtOAc/hexanes) afforded the titlecompound as a white solid (33 mg, 69%). ¹H NMR (400 MHz, CDCl₃) δ 8.75(d, J=2.0 Hz, 1H), 8.01 (s, 1H), 7.71 (d, J=9.0 Hz, 1H), 7.49 (s, 1H),7.45 (d, J=2.7 Hz, 1H), 7.38-7.27 (m, 4H), 5.19 (s, 2H), 3.79 (s, 2H),3.73 (s, 3H). [M+H]=342.2.

Example 55 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide

Ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 100mg, 0.28 mmol) was dissolved in a 7N solution of ammonia in MeOH (40 mL)and stirred at ambient temperature overnight. The reaction mixture wasconcentrated under reduced pressure to afford a yellow solid. Et₂O wasadded and the yellow precipitate was collected by filtration. DCM wasadded and the off white precipitate was isolated by filtration, this wasrepeated to yield the title compound as an off white solid (59 mg, 64%).¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (d, J=2.0 Hz, 1H), 8.14 (d, J=2.0 Hz,1H), 7.92 (d, J=9.0 Hz, 1H), 7.64 (d, J=1.6 Hz, 2H), 7.57-7.44 (m, 4H),7.37 (dd, J=2.7, 9.0 Hz, 1H), 7.08-7.02 (m, 1H), 5.34 (s, 2H), 3.60 (s,2H). [M+H]=327.2.

Example 56 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)ethanol

To a cooled, −78° C., solution of ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, 50 mg, 0.14mmol) in THF (1.5 mL), under an atmosphere of nitrogen, was added LiAlH₄(2.4 M in THF, 0.1 mL, 0.24 mmol). The reaction was stirred for 7 hbefore being quenched with 1N NaOH (aq.). The crude reaction mixture wasfiltered through CELITE® and the aqueous layer was extracted with EtOAc.The combined organic fractions were concentrated onto silica andpurification (FCC, SiO₂, 0-5%, MeOH/DCM) afforded the title compound asa yellow solid (29 mg, 66%). ¹H NMR (400 MHz, CDCl₃) δ 8.71 (d, J=2.0Hz, 1H), 7.92 (s, 1H), 7.67 (d, J=9.0 Hz, 1H), 7.50 (s, 1H), 7.42 (d,J=2.3 Hz, 1H), 7.38-7.27 (m, 4H), 5.18 (s, 2H), 4.02-3.90 (m, 2H), 3.02(t, J=6.3 Hz, 2H). [M+H]=314.3.

Example 57 2-(7-((3-Fluorobenzyl)oxy)quinolin-3-yl)acetamide

The title compound was prepared in a manner analogous to Example 55,substituting ethyl 2-(7-((3-fluorobenzyl)oxy)quinolin-3-yl)acetate(Example 52) for ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate(Example 51). ¹H NMR (400 MHz, DMSO-d₆) δ 8.69 (d, J=2.3 Hz, 1H), 8.08(d, J=2.0 Hz, 1H), 7.86 (d, J=9.0 Hz, 1H), 7.65-7.54 (m, 1H), 7.50-7.39(m, 2H), 7.38-7.27 (m, 3H), 7.21-7.13 (m, 1H), 7.03-6.95 (m, 1H), 5.29(s, 2H), 3.55 (s, 2H). [M+H]=311.3.

Example 58 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)acetamide

The title compound was prepared in a manner analogous to Example 55,substituting ethyl 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)acetate(Example 53) for ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate(Example 51). ¹H NMR (400 MHz, DMSO-d₆) δ 8.74 (d, J=2.3 Hz, 1H), 8.13(s, 1H), 7.90 (d, J=8.6 Hz, 1H), 7.71-7.58 (m, 3H), 7.50 (d, J=2.3 Hz,1H), 7.37-7.23 (m, 3H), 7.11-6.97 (m, 1H), 5.29 (s, 2H), 3.60 (s, 2H).[M+H]=311.3.

Example 59 Ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate

To a cooled solution, 0° C., under an atmosphere of nitrogen, of ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51, procedure1, 390 mg, 1.1 mmol) in THF (11 mL) was added KHMDS (5.48 mL, 0.5 Msoln. in toluene, 2.74 mmol). The reaction mixture was stirred at 0° C.for one hour. Methyl iodide (283 μL, 4.54 mmol) was added and thereaction was warmed to ambient temperature. After 3 h the reaction wasquenched by the addition of saturated ammonium chloride solution and theorganics were extracted with EtOAc. The combined organic extracts werewashed with brine and concentrated onto silica. Purification (FCC, SiO₂,0-40%, EtOAc/hexanes) afforded the title compound as a clear oil (300mg, 71%). ¹H NMR (400 MHz, CDCl₃) δ 8.84 (d, J=2.7 Hz, 1H), 8.00 (d,J=2.3 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=2.3 Hz,1H), 7.32 (d, J=5.9 Hz, 4H), 5.19 (s, 2H), 4.14 (q, J=7.0 Hz, 2H), 1.69(s, 6H), 1.18 (t, J=7.0 Hz, 3H). [M+H]=384.3.

Example 60 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-1-ol

The title compound was prepared in a manner analogous to Example 56,substituting ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate (Example 59)for ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate (Example 51).¹H NMR (400 MHz, CDCl₃) δ 8.89 (d, J=2.0 Hz, 1H), 8.00 (d, J=2.3 Hz,1H), 7.67 (d, J=9.0 Hz, 1H), 7.50 (s, 1H), 7.40-7.29 (m, 4H), 7.24 (d,J=2.7 Hz, 1H), 5.18 (s, 2H), 3.75 (s, 2H), 1.45 (s, 6H). [M+H]=342.3.

Example 61 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanamide

Step A: 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoic acid.To a solution of ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate (Example 59,300 mg, 0.78 mmol) in THF (2.6 mL) and MeOH (2.6 mL) was added LiOH (54mg, 2.25 mmol) in H₂O (2.6 mL). The reaction was stirred at ambienttemperature overnight. The solvents were removed under reduced pressure,10% HCl (aq.) (5 mL) was added and the precipitate was collected anddried under vacuum, the crude product was used without furtherpurification in the next step.

Step B: 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoylchloride. To a solution of2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoic acid in DCM(8 mL) was added oxalyl chloride (208 μL, 2.34 mmol) followed by 3 dropsof DMF. After 30 minutes, additional oxalyl chloride (2 mL, 22.5 mmol)was added. After 30 minutes stifling at ambient temperature the reactionwas concentrated under reduced pressure and dried under high vacuum toafford the title compound as an oil. The crude product was used withoutfurther purification in the next step.

Step C: 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanamide. Toa solution of 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoylchloride in THF (3 mL) was added ammonium hydroxide (10 mL). Thereaction was stirred overnight at ambient temperature. The reactionmixture was concentrated onto silica and purification (FCC, SiO₂, 0-10%,MeOH/DCM) afforded the title compound as a white solid (28 mg, 10%). ¹HNMR (400 MHz, CDCl₃) δ 8.88 (d, J=2.7 Hz, 1H), 8.07 (d, J=2.3 Hz, 1H),7.73 (d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.45 (d, J=2.3 Hz, 1H), 7.39-7.27(m, 4H), 5.34-5.22 (m, 2H), 5.19 (s, 2H), 1.71 (s, 6H). [M+H]=355.3.

Example 622-(7-((2-(Trifluoromethyl)pyridin-4-yl)methoxy)quinolin-3-yl)acetamide

Step A: Ethyl2-(7-((2-(trifluoromethyl)pyridin-4-yl)methoxy)quinolin-3-yl)acetate. Toa solution of 4-(chloromethyl)-2-(trifluoromethyl)pyridine (162.06 mg,0.83 mmol) in DMF (5 mL) was added ethyl2-(7-hydroxyquinolin-3-yl)acetate (Intermediate 2, 150 mg, 0.55 mmol)and Cs₂CO₃ (356 mg, 1.10 mmol). The reaction was stirred at ambienttemperature for 16 h. A mixture of mono benzylated and bisbenzylatedproducts were observed. Cesium carbonate was filtered off and DMF wasremoved under reduced pressure. Purification (FCC, SiO₂, 0-50%,EtOAc/hexanes) afforded a mixture of methyl and ethyl esters along with25% of bis-benzylated product. The mixture was advanced into the nextreaction.

Step B:2-(7-((2-(Trifluoromethyl)pyridin-4-yl)methoxy)quinolin-3-yl)acetamide.Ethyl2-(7-((6-(trifluoromethyl)pyridin-3-yl)methoxy)quinolin-3-yl)acetate(0.15 g, 0.30 mmol) and ammonia in MeOH (7 N, 0.13 g, 7.40 mmol) werecombined and stirred at ambient temperature for 3 days. MeOH was removedunder reduced pressure. Purification by FCC (SiO₂, 0-20%, MeOH/DCM)afforded the title compound as a white solid (0.95 g, 88% yield over 2steps). ¹H NMR (400 MHz, DMSO-d₆) δ 8.82 (d, J=4.8 Hz, 1H), 8.73 (d,J=2.0 Hz, 1H), 8.13 (s, 1H), 8.04 (s, 1H), 7.93 (d, J=8.8 Hz, 1H), 7.86(d, J=4.8 Hz, 1H), 7.60 (br. s., 1H), 7.48 (d, J=2.3 Hz, 1H), 7.42 (dd,J=2.4, 8.9 Hz, 1H), 7.00 (br. s., 1H), 5.51 (s, 2H), 3.59 (s, 2H).[M+H]=363.2

Example 63 1-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate(Example 51) for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 8.72 (d, J=2.0 Hz, 1H), 7.94 (d, J=2.0 Hz, 1H), 7.70(d, J=9.0 Hz, 1H), 7.49 (s, 1H), 7.43 (d, J=2.3 Hz, 1H), 7.38-7.26 (m,4H), 5.18 (s, 2H), 2.91 (s, 2H), 1.28 (s, 6H). [M+H]=342.2.

Example 64 7-((3-Chlorobenzyl)oxy)quinoline-3-carboxamide

The title compound was prepared in a manner analogous to Example 55,substituting ethyl 7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate(Example 3) for ethyl 2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate(Example 51). ¹H NMR (400 MHz, DMSO-d₆) δ 9.33 (s, 1H), 9.13-8.96 (m,1H), 8.31-8.16 (m, 1H), 7.64 (br. s., 2H), 7.48 (d, J=7.0 Hz, 4H),6.50-5.65 (m, 2H), 5.40 (s, 2H). [M+H]=313.2.

Example 652-{7-[(4-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol

Step A. Ethyl 7-((4-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate.To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate(Intermediate 4, 3.0 g, 13.75 mmol) in DMF (70 mL) was added Cs₂CO₃(8.96 g, 0.03 mol), followed by 4-fluorobenzyl chloride (2.42 mL, 0.02mol). The reaction was stirred at ambient temperature for 72 h. Thecrude reaction mixture was poured into EtOAc and water. The aqueouslayer was extracted with EtOAc and the combined organic fractions werewashed with brine and concentrated under reduced pressure onto silica.Purification (FCC, SiO₂, 0-60%, EtOAc/hexanes) afforded the titlecompound as a white solid (3.0 g, 67%) ¹H NMR (400 MHz, CDCl₃) δ 9.45(d, J=1.6 Hz, 1H), 8.97 (s, 1H), 8.85 (d, J=2.3 Hz, 1H), 7.72 (d, J=2.0Hz, 1H), 7.48 (dd, J=5.5, 7.8 Hz, 2H), 7.12 (t, J=8.6 Hz, 2H), 5.22 (s,2H), 4.48 (q, J=7.3 Hz, 2H), 1.46 (t, J=7.0 Hz, 3H). [M+H]=327.2

Step B: The title compound was prepared in a manner analogous to Example27, substituting ethyl7-((4-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate for7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 9.07 (d, J=2.0 Hz, 1H), 8.76 (d, J=2.7 Hz, 1H), 8.36(d, J=2.3 Hz, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.45 (dd, J=5.3, 8.4 Hz, 2H),7.08 (t, J=8.6 Hz, 2H), 5.16 (s, 2H), 1.70 (s, 6H). [M+H]=313.2.

Example 667-[(4-Fluorophenyl)methoxy]-3-(2-hydroxypropan-2-yl)quinolin-1-ium-1-olate

To a cooled, 0° C., solution of2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol (Example 27, 0.063mg, 0.2 mmol) in DCM (2 mL) was added 3-chloroperoxybenzoic acid (0.068mg, 0.4 mmol). The reaction was slowly warmed to ambient temperature andstirred for 2 h before being quenched with aq. sat. NaHCO₃. The aqueouslayer was extracted with DCM. The combined organic layers wereconcentrated under reduced pressure onto silica. Purification (FCC,SiO₂, 0-10%, MeOH/DCM) afforded the title compound as a light yellow oil(51 mg, 82%). ¹H NMR (400 MHz, CDCl₃) δ 8.61 (d, J=1.5 Hz, 1H), 7.94 (d,J=2.5 Hz, 1H), 7.60-7.37 (m, 3H), 7.36-7.23 (m, 1H), 7.22-7.04 (m, 3H),5.22 (s, 2H), 1.62 (s, 6H). [M+H]=328.2.

Example 67 7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide

Step A. Ethyl 7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate.To a solution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate(Intermediate 4, 1.0 g, 4.59 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.2g, 6.75 mmol), followed by 3-fluorobenzyl chloride (0.6 mL, 5.02 mmol).The reaction was stirred at ambient temperature for 72 h. The crudereaction mixture was poured into EtOAc and water. The aqueous later wasextracted with EtOAc and the combined organic fractions were washed withbrine and concentrated under reduced pressure onto silica. Purification(FCC, SiO₂, 0-60%, EtOAc/hexanes) afforded the title compound as a whitesolid (1.0 g, 69%). ¹H NMR (400 MHz, CDCl₃) δ 9.44 (t, J=2.0 Hz, 1H),9.00-8.94 (m, 1H), 8.88 (t, J=2.3 Hz, 1H), 7.74-7.65 (m, 1H), 7.47-7.33(m, 1H), 7.28-7.26 (m, 1H), 7.21 (d, J=9.4 Hz, 1H), 7.07 (t, J=8.6 Hz,1H), 5.25 (s, 2H), 4.59-4.38 (m, 2H), 1.52-1.41 (m, 3H). [M+H]=327.2.

Step B. 7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide.Ethyl 7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate (100 mg,0.31 mmol) was suspended in 7N ammonia in MeOH (4.0 mL) and was stirredovernight at ambient temperature. Concentration onto silica andpurification (FCC, SiO₂, 0-10%, MeOH/DCM) afforded the title compound asa white solid (11 mg, 12%). ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J=2.3Hz, 1H), 8.91 (d, J=2.7 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.36 (br. s.,1H), 7.92 (d, J=2.7 Hz, 1H), 7.71 (br. s., 1H), 7.51-7.43 (m, 1H),7.42-7.36 (m, 2H), 7.20 (dt, J=2.3, 8.6 Hz, 1H), 3.30 (d, J=1.2 Hz, 2H).[M+H]=298.2.

Example 68 7-((4-Fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide

The title compound was prepared in a manner analogous to Example 67,substituting 4-fluorobenzyl chloride for 3-fluorobenzyl chloride in StepA. ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J=2.0 Hz, 1H), 8.87 (d, J=2.7Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.43-8.28 (m, 1H), 7.93 (d, J=2.7 Hz,1H), 7.74-7.66 (m, 1H), 7.60 (dd, J=5.9, 8.2 Hz, 2H), 7.26 (t, J=8.6 Hz,2H), 5.35 (s, 2H). [M+H]=298.2.

Example 69 7-((3-Chlorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide

The title compound was prepared in a manner analogous to Example 67,substituting 3-chlorobenzyl chloride for 3-fluorobenzyl chloride in StepA. ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J=2.0 Hz, 1H), 8.90 (d, J=2.7Hz, 1H), 8.82 (dd, J=0.8, 2.0 Hz, 1H), 8.40-8.28 (m, 1H), 7.93-7.88 (m,1H), 7.74-7.66 (m, 1H), 7.63 (s, 1H), 7.53-7.39 (m, 3H), 5.40-5.37 (m,2H). [M+H]=314.1

Example 70 7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide

The title compound was prepared in a manner analogous to Example 67,substituting 3,4-difluorobenzyl chloride for 3-fluorobenzyl chloride inStep A. ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (d, J=2.3 Hz, 1H), 8.89 (d,J=2.7 Hz, 1H), 8.82 (d, J=2.0 Hz, 1H), 8.36 (br s, 1H), 7.93 (d, J=2.7Hz, 1H), 7.71 (br s, 1H), 7.68-7.60 (m, 1H), 7.50 (td, J=8.4, 10.7 Hz,1H), 7.44-7.34 (m, 1H), 5.36 (s, 2H). [M+H]=316.2.

Example 717-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide

The title compound was prepared in a manner analogous to Example 67,substituting 3-chloro-4-fluorobenzyl chloride for 3-fluorobenzylchloride in Step A. ¹H NMR (400 MHz, DMSO-d₆) δ 9.32 (d, J=2.3 Hz, 1H),8.90 (d, J=2.7 Hz, 1H), 8.82 (d, J=1.6 Hz, 1H), 8.39-8.33 (m, 1H), 7.93(d, J=2.3 Hz, 1H), 7.81 (dd, J=2.2, 7.2 Hz, 1H), 7.74-7.67 (m, 1H),7.60-7.55 (m, 1H), 7.51-7.43 (m, 1H), 5.36 (s, 2H). [M+H]=332.2.

Example 727-[(3-Chlorophenyl)methoxy]-N-methyl-1,5-naphthyridine-3-carboxamide

The title compound was prepared in a manner analogous to Example 67,substituting 3-chlorobenzyl chloride for 3-fluorobenzyl chloride in StepA and substituting a 2.0 M solution of methylamine in MeOH for theammonia solution in Step B. ¹H NMR (400 MHz, DMSO-d₆) δ 9.31 (d, J=2.0Hz, 1H), 8.98-8.69 (m, 3H), 7.94 (d, J=2.5 Hz, 1H), 7.65 (s, 1H),7.57-7.35 (m, 3H), 5.41 (s, 2H), 2.87 (d, J=4.5 Hz, 3H). [M+H]=328.6.

Example 73 (7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol

Step A. Ethyl7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate. To asolution of ethyl 7-hydroxy-1,5-naphthyridine-3-carboxylate(Intermediate 4, 1.0 g, 4.5 mmol) in DMF (20 mL) was added Cs₂CO₃ (2.2g, 6.75 mmol), followed by 3,4-difluorobenzyl bromide (0.682 mL, 5.02mmol). The reaction was stirred at ambient temperature for 72 h. Thecrude reaction mixture was poured into EtOAc and water. The aqueouslayer was extracted with EtOAc and the combined organic fractions werewashed with brine and concentrated under reduced pressure onto silica.Purification (FCC, SiO₂, 0-60%, EtOAc/hexanes) afforded the titlecompound as a white solid (1.05 g, 64%) ¹H NMR (400 MHz, CDCl₃) δ9.48-9.41 (m, 1H), 8.97 (s, 1H), 8.89-8.82 (m, 1H), 7.69 (s, 1H),7.37-7.29 (m, 1H), 7.25-7.19 (m, 2H), 5.20 (s, 2H), 4.54-4.40 (m, 2H),1.51-1.41 (m, 3H). [M+H]=345.2.

Step B. (7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol. Toa solution of ethyl7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate (0.3 g, 0.87mmol) in THF (6 mL) at 0° C. and under nitrogen atmosphere was addedlithium aluminum hydride (0.4 mL, 0.8 mmol, 2 M in THF). The mixture wasallowed to warm to ambient temperature and stirred at ambienttemperature for an additional 15 h. The reaction was quenched with waterslowly and pH adjusted to ˜3 with 1 M HCl. The resulting mixture wasextracted with EtOAc and the organic layer separated, washed with brine,dried and concentrated under reduced pressure. The pH of the aqueouslayer was adjusted to ˜8 with saturated NaHCO₃ solution and theresulting suspension filtered. The filtered solid combined with theprevious product were purified (FCC, SiO₂, 0-100%, EtOAc/hexanes) toafford the title compound as a yellow solid (90 mg, 27%). ¹H NMR (400MHz, DMSO-d₆) δ 8.88 (d, J=1.6 Hz, 1H), 8.80 (d, J=2.3 Hz, 1H), 8.23 (s,1H), 7.86 (d, J=2.7 Hz, 1H), 7.69-7.58 (m, 1H), 7.53-7.44 (m, 1H), 7.40(br. s., 1H), 5.32 (s, 2H), 4.73 (s, 2H). [M+H]=303.3.

Example 742-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}acetonitrile

Step A. (7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methylmethanesulfonate. To a solution of(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol (Example 73,90 mg, 0.3 mmol) in DCM (4 mL) was added methanesulfonyl chloride (0.05mL, 0.61 mmol) followed by TEA (0.06 mL, 0.43 mmol). The reactionmixture was stirred at RT for 1 h and quenched with saturated NaHCO₃solution. The mixture was extracted with DCM (2×) and the combinedorganic layers were dried, filtered and concentrated under reducedpressure. Purification (FCC, SiO₂, 0-80%, EtOAc/hexanes) afforded thetitle compound as a white solid (73 mg, 64%). [M+H]=381.1.

Step B.2-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}acetonitrile. Asolution of (7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methylmethanesulfonate (73 mg, 0.19 mmol) and sodium cyanide (12 mg, 0.25mmol) in DMSO (2 mL) was heated at 60° C. for 15 min. The reaction wascooled to RT and then diluted with water. The resulting light brownsolid was filtered to afford the desired product (45 mg, 75%). ¹H NMR(400 MHz, DMSO-d₆) δ 8.89 (s, 1H), 8.84 (d, J=2.3 Hz, 1H), 8.32 (s, 1H),7.90 (d, J=2.3 Hz, 1H), 7.69-7.59 (m, 1H), 7.53-7.44 (m, 1H), 7.43-7.36(m, 1H), 5.33 (s, 2H), 4.30 (s, 2H). [M+H]=312.15

Example 753-[(4-Fluorophenyl)methoxy]-7-(2-fluoropropan-2-yl)-1,5-naphthyridine

The title compound was prepared in a manner analogous to Example 41,substituting2-(7-((4-fluorobenzyl)oxy)-1,5-naphthyridin-3-yl)propan-2-ol (Example65) for 2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol (Example27). ¹H NMR (400 MHz, CDCl₃) δ 9.02 (d, J=2.0 Hz, 1H), 8.84 (d, J=2.8Hz, 1H), 8.33 (s, 1H), 7.73 (d, J=2.8 Hz, 1H), 7.51 (dd, J=5.5, 8.3 Hz,2H), 7.15 (t, J=8.7 Hz, 2H), 5.24 (s, 2H), 2.01-1.78 (m, 6H).[M+H]=315.2.

Example 762-{7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl7-((3-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 9.09 (d, J=2.3 Hz, 1H), 8.80 (d, J=2.7 Hz, 1H),8.40-8.36 (m, 1H), 7.66 (d, J=2.7 Hz, 1H), 7.42-7.33 (m, 1H), 7.28-7.25(m, 1H), 7.23-7.16 (m, 1H), 7.09-6.99 (m, 1H), 5.22 (s, 2H), 1.71 (s,6H). [M+H]=313.2.

Example 772-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate (Example 73,product from Step A) for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 9.09 (d, J=2.3 Hz, 1H), 8.78 (d, J=2.7 Hz, 1H), 8.38(d, J=2.3 Hz, 1H), 7.65 (d, J=2.7 Hz, 1H), 7.39-7.27 (m, 1H), 7.22-7.15(m, 2H), 5.16 (s, 2H), 1.71 (d, J=0.8 Hz, 6H). [M+H]=331.2.

Example 782-{7-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl7-((3-chloro-4-fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate forethyl 7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹HNMR (400 MHz, CDCl₃) δ 9.12 (d, J=2.3 Hz, 1H), 8.85-8.72 (m, 1H),8.46-8.36 (m, 1H), 7.70-7.64 (m, 1H), 7.61-7.53 (m, 1H), 7.42-7.34 (m,1H), 7.24-7.17 (m, 1H), 5.18 (s, 2H). [M+H]=347.1

Example 792-{7-[(3-Chlorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol

The title compound was prepared in a manner analogous to Example 27,substituting ethyl7-((3-chlorobenzyl)oxy)-1,5-naphthyridine-3-carboxylate for ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate (Example 2). ¹H NMR(400 MHz, CDCl₃) δ 9.09 (t, J=2.0 Hz, 1H), 8.80 (t, J=2.3 Hz, 1H),8.44-8.35 (m, 1H), 7.66 (s, 1H), 7.49 (s, 1H), 7.41-7.31 (m, 3H), 5.20(s, 2H), 1.79-1.68 (m, 6H). [M+H]=329.2.

Example 802-(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamide

Step A. 3-Bromo-7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine. To amixture of (3,4-difluorophenyl)methanol (119 μL, 1.04 mmol) and3,7-dibromo-1,5-naphthyridine (Intermediate 3, 200 mg, 0.69 mmol) in NMP(1 mL) at 100° C. under a nitrogen atmosphere was added a slurry ofsodium hydride (69.45 mg, 1.74 mmol) in NMP (1 mL) dropwise. Thesolution was allowed to stir at 100° C. for 3 h. Upon completion thereaction was cooled and water was added to afford a solid precipitate.The solid was collected by filtration to give the title compound (130mg, 53.3%) as a crude brown solid, which used without furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.93 (s, 1H), 8.82 (d, J=2.5 Hz,1H), 8.54 (s, 1H), 7.66 (d, J=2.0 Hz, 1H), 7.41-7.31 (m, 1H), 7.27-7.16(m, 2H), 5.19 (s, 2H). [M+H]=351.1.

Step B. Ethyl2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetate.3-Bromo-7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridine (3.20 g, 9.11mmol), Pd₂(dba)₃ (41.72 mg, 0.05 mmol), tri-tert-butylphosphoniumtetrafluoroborate (290.84 mg, 1 mmol), potassium phosphate (5.42 g,25.52 mmol), 1,4,7,10,13,16-hexaoxacyclooctadecane (1.2 g, 4.56 mmol),and diethyl malonate (9.17 mL, 60.15 mmol) were added to a microwavevial, which was capped and purged with nitrogen for several minutes thenheated to 115° C. for 19 h. The reaction was cooled to ambienttemperature then water and EtOAc were added. The layers were separatedand the aqueous solution was extracted with EtOAc and DCM. The combinedorganic layers were washed with brine then dried (Na₂SO₄). The solventwas removed under reduced pressure. Purification (FCC, SiO₂, 0-70%,EtOAc/hexanes) afforded the title compound as a pure beige solid (1.76g, 53.8%). ¹H NMR (400 MHz, CDCl₃) δ 8.84 (dd, J=18.1, 2.5 Hz, 2H), 8.27(d, J=1.4 Hz, 1H), 7.68 (d, J=2.6 Hz, 1H), 7.47-7.30 (m, 1H), 7.26-7.17(m, 2H), 5.20 (s, 2H), 4.22 (q, J=7.2 Hz, 2H), 3.86 (s, 2H), 1.30 (t,J=7.2 Hz, 3H). [M+H]=359.2.

Step C: 2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamide.Ethyl 2-(7-((3,4-difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetate (1.95g, 5.44 mmol) was treated with a solution of ammonia in MeOH (7 M, 30mL, 245 mmol). The slurry was stirred at ambient temperature for 30 h.The resulting precipitate was filtered and washed with MeOH to give thetitle compound as a cream colored solid. The crude product was azeotropedried with toluene to remove traces of ammonia then dried on high vacuumfor 48 h to give the title compound (1.79 g, 82%) as a pure white solid.¹H NMR (400 MHz, DMSO-d₆) δ 8.81 (t, J=2.0 Hz, 2H), 8.21 (d, J=1.4 Hz,1H), 7.88 (d, J=2.6 Hz, 1H), 7.75-7.58 (m, 2H), 7.50 (td, J=8.4, 10.7Hz, 1H), 7.45-7.36 (m, 1H), 7.05 (br s, 1H), 5.34 (s, 2H), 3.66 (s, 2H).[M+H]=330.2.

Example 812-(7-((6-(Trifluoromethyl)pyridin-2-yl)methoxy)-1,5-naphthyridin-3-yl)acetamide

The title compound was prepared in a manner analogous to Example 80,substituting (6-(trifluoromethyl)pyridin-2-yl)methanol for(3,4-difluorophenyl)methanol in Step A. ¹H NMR (400 MHz, DMSO-d₆) δ 8.88(d, J=2.9 Hz, 1H), 8.82 (d, J=1.9 Hz, 1H), 8.27-8.14 (m, 2H), 7.98 (d,J=7.9 Hz, 1H), 7.95-7.88 (m, 2H), 7.64 (br s, 1H), 7.05 (br. s., 1H),5.53 (s, 2H), 3.66 (s, 2H). [M+H]=363.2.

Example 822-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide

Ethyl2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetate(Example 51, product from Step D, 200 mg, 0.54 mmol) was dissolved in a7 N solution of ammonia in methanol (10 mL) and stirred at roomtemperature for 2 weeks. The resulting precipitate was collected byfiltration, washed with methanol (3 mL) and was dried under vacuum togive the title compound as a white solid (111 mg, 60%). ¹H NMR (400 MHz,DMSO-d₆) δ 10.08 (s, 1H), 7.53-7.33 (m, 5H), 7.06 (d, J=8.3 Hz, 1H),6.85 (br s, 1H), 6.57 (dd, J=2.4, 8.3 Hz, 1H), 6.51 (d, J=2.4 Hz, 1H),5.05 (s, 2H), 2.93-2.70 (m, 2H), 2.71-2.54 (m, 2H), 2.11 (dd, J=8.5,15.2 Hz, 1H). [M+H]=345.1.

Example 832-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetamide

Ethyl 2-(7-((3-chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetate(Example 51, product from Step E, 200 mg, 0.54 mmol) was dissolved in a7 N solution of ammonia in methanol (10 mL) and stirred at roomtemperature for 2 weeks. The resulting precipitate was collected byfiltration, washed with methanol (3 mL) and was dried under vacuum togive the title compound as a white solid (136 mg, 74%). ¹H NMR (400 MHz,DMSO-d₆) δ 11.68 (s, 1H), 7.70 (s, 1H), 7.54 (s, 2H), 7.43 (s, 3H), 7.35(br s, 1H), 6.86 (s, 2H), 6.85 (br s, 1H), 5.16 (s, 2H), 3.27 (s, 2H).[M+H]=343.1.

Pharmacological Examples

The present disclosure will be further illustrated by the followingpharmacological examples. These examples are understood to be exemplaryonly and are not intended to limit the scope of the invention disclosedherein.

Enzymatic Assay

The MAO enzymatic assay was performed according to the fluorometricmethod described by Matsumoto and colleagues (Matsumoto et al., Clin.Biochem. 1985, 18, 126-129) with the following modifications. Humanrecombinant MAO-A and MAO-B expressed in insect cells were used. Forboth assays, test compound and/or vehicle were preincubated withpurified enzyme in phosphate buffer pH 7.4 for 15 minutes at 37° C. Thereaction was initiated by addition of 50 μm kynuramine. Following a 60minute incubation period, the reaction was terminated by the addition of6 N NaOH. The amount of 4-hydroxyquinoline that formed was determined byspectrofluorimetrically at 325 nm/465 nm.

Results were converted to percent inhibition, and the EC50 (M) for eachreaction was determined using the XLfit program from IDBS (ID BusinessSolutions Ltd., 2 Occam Court, Surrey Research Park, Guildford, Surrey,GU2 7QB UK). The EC50 represents the concentration of a compound where50% of its maximal effect is observed. The pEC₅₀ is defined as thenegative logarithm of the EC₅₀; a higher pEC50 value thereforecorresponds to higher potency in the assay.

Pharmacological Example 1 MAO-B Inhibition

Representative compounds of the invention were evaluated in the MAO-Benzymatic assay. Typically, the compounds of the invention show MAO-Binhibitory properties at a concentration of 0.1 to 10 μM, typically at5-100%.

As depicted in the following Table, these inhibitory properties weremirrored by pEC₅₀ values ranging from 5 (meaning 10⁻⁵ M or 10 μM) togreater than 7 (meaning less than 10⁻⁷ M or 0.1 μM).

MAO-B (pEC₅₀) Example Number >7 1, 2, 3, 4, 5, 7, 9, 12, 13, 14, 15, 16,17, 18, 19, 20, 21, 22, 23, 24, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35,36, 37, 40, 41, 42, 43, 44, 45, 46, 47, 50, 54, 55, 56, 57, 58, 60, 61,62, 64, 65, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 82,83 6-7 6, 8, 10, 11, 25, 38, 39, 48, 51, 53, 59, 66, 81 5-6 49, 52, 63

In specific embodiments, a compound of the present invention shows MAO-Binhibitory properties at a concentration of less than about 50 μM, 40μM, 35 μM, 25 μM, 20 μM, 15 μM, 10 μM, 5 μM, 1 μM, 500 nM, 400 nM, 300nM, 200 nM, 100 nM, 75 nM, 50 nM, 25 nM, 10 nM, 5 nM, or 1 nM.

Pharmacological Example 2 MAO-B Selectivity

Exemplary compounds of the present invention showed greater selectivityfor MAO-B over MAO-A, as indicated in the following Table.

MAO-A/MAO-B Example Number >200 12, 14, 15, 16, 27 >100-200 2, 5, 7, 9,13, 17  >10-100 1, 3, 6, 8, 10, 18, 24, 25  1-10 4, 11

In specific embodiments, a compound of the present invention showsgreater than 2-fold, 5-fold, 10-fold, 50-fold, 100-fold, or 200-fold,500-fold, or 1000-fold selectivity for MAO-B over MAO-A.

Biological Examples

The present disclosure will be further illustrated by the followingbiological examples. These examples are understood to be exemplary onlyand are not intended to limit the scope of the invention disclosedherein.

Behavioral Assays

Numerous behavioral assays are available to assess the ability of acandidate compound to enhance memory formation, including contextualconditioning (e.g., fear conditioning), temporal conditioning (e.g.,trace conditioning), and object recognition. Other non-limiting examplesof appropriate assays to assess memory include those that incorporate orrelate to multiple training sessions, spaced training sessions,contextual fear training with single or multiple trials, trace fearconditioning with single or multiple trials, contextual memorygenerally, temporal memory, spatial memory, episodic memory, passiveavoidance memory, active avoidance memory, food preference memory,conditioned taste avoidance, and social recognition memory.

The behavioral assays can also be used in accordance with the presentinvention, as will be understood by those of ordinary skill in the art.These assays can be directed towards the evaluation of, withoutlimitation, hippocampus-, cortex, and/or amygdala-dependent memoryformation or cognitive performance.

Biological Example 1 Effect of MAO-B Inhibitors on Contextual MemoryRationale

Contextual fear conditioning is a form of associative learning in whichanimals learn to recognize a training environment (conditioned stimulus,CS) that has been previously paired with an aversive stimulus such asfoot shock (unconditioned stimulus, US). When exposed to the samecontext at a later time, conditioned animals show a variety ofconditional fear responses, including freezing behavior. The percent oftime during the test that the animal exhibits such freezing provides aquantitative measure of the contextual associative memory (e.g.,Fanselow, Behav. Neurosci. 1984, 98, 269-277; Fanselow, Behav. Neurosci.1984, 98, 79-95; and Phillips and LeDoux, Behav. Neurosci. 1992, 106,274-285).

Contextual conditioning has been extensively used to investigate theneural substrates mediating fear-motivated learning (e.g., Phillips andLeDoux, Behav. Neurosci. 1992, 106, 274-285; Kim et al., Behav.Neurosci. 1993, 107, 1093-1098; and Bourtchouladze et al., Learn. Mem.1998, 5, 365-374). Studies in mice and rats provided evidence forfunctional interaction between hippocampal and nonhippocampal systemsduring contextual conditioning training (e.g., Maren et al., Behav.Brain Res. 1997, 88, 261-274; Maren et al., Neurobiol. Learn. Mem. 1997,67, 142-149; and Frankland et al., Behav. Neurosci. 1998, 112, 863-874).Specifically, post-training lesions of the hippocampus (but notpre-training lesions) greatly reduced contextual fear, implying that: 1)the hippocampus is essential for contextual memory but not forcontextual learning per se and 2) in the absence of the hippocampusduring training, non-hippocampal systems can support contextualconditioning.

Contextual conditioning has been extensively used to study the impact ofvarious mutations on hippocampus-dependent learning, as well as strainand genetic background differences in mice (e.g., Bourtchouladze et al.,Cell 1994, 79, 59-68; Bourtchouladze et al., Learn Mem. 1998, 5,365-374; Kogan et al., Current Biology 1997, 7, 1-11; Silva et al.,Current Biology 1996, 6, 1509-1518; Abel et al., Cell 1997, 88, 615-626;Giese et al., Science 1998, 279, 870-873; Logue et al., Neuroscience1997, 80, 1075-1086; Chen et al., Behav. Neurosci. 1996, 110, 1177-1180;and Nguyen et al., Learn Mem. 2000, 7, 170-179).

Because robust learning can be triggered with a few minutes trainingsession, contextual conditioning has been especially useful to study thebiology of temporally distinct processes of short- and long-term memory(e.g., Kim et al., Behav. Neurosci. 1993, 107, 1093-1098; Bourtchouladzeet al., Cell 1994, 79, 59-68; Abel et al., Cell 1997, 88, 615-626; Logueet al., Behav. Neurosci. 1997, 111, 104-113; Bourtchouladze et al.,Learn. Mem. 1998, 5, 365-374 and Nguyen et al., Learn. Mem. 2000, 7,170-179). As such, contextual conditioning provides an excellent modelto evaluate the effects of novel drug compounds on hippocampal-dependentmemory formation.

Procedures

Previous investigations have established that training with 1× or2×CS-US pairings induces sub-maximal (weak) memory in wild-type mice(e.g., U.S.2009/0053140; Tully et al., Nat. Rev. Drug Discov. 2003, 2,267-77; and Bourtchouladze et al. Learn. Mem. 1998, 5, 365-374).Accordingly, contextual conditioning in this study was performed asdescribed by Bourtchouladze et al., Cell 1994, 79, 59-68.

Young-adult (10-12 weeks old) C57BL/6 male mice and Sprague Dawley malerats were used. Mice and rats were group-housed in standard laboratoryand maintained on a 12:12 light-dark cycle. The experiments were alwaysconducted during the light phase of the cycle. With the exception oftesting times, the mice had ad libidum access to food and water. Toassess contextual memory, a modified contextual fear conditioning taskoriginally developed for evaluation of memory in CREB knock-out mice wasused (Bourtchouladze et al., 1994). Training sessions are comprised of abaseline period in the conditioning chamber (Med Associates, Inc.)followed by presentation of unconditioned stimuli (1-5 footshocks eachat 0.2-1.0 mA for 2-sec) spaced at 60-sec intervals. Thirty secondsfollowing the last shock, the animal is returned to the home cage. Oneto 7 days later, the animals are returned to the chamber and freezingbehavior is scored. Freezing (complete immobility except respiration) isscored by Video Freeze software (Med Associates, Inc.) over an 8 minutetest period. Treatment with cognition enhancers are expected tosignificantly increase freezing when compared with controls.

All experiments were designed and performed in a counterbalancedfashion. In each experiment, the experimenter was unaware (blind) to thetreatment of the subjects during training and testing. Training and testsessions were recorded as digital video files. Data were analyzed byone-way ANOVA with appropriate post-hoc tests using GraphPad Prismsoftware package.

Results

Exemplary compounds were found to enhance contextual memory in the fearconditioning assay. Significant enhancing effects were seen at severalconcentrations, including 0.01 mg/kg, 0.03 mg/kg, and 1.0 mg/kg.

Biological Example 2 Effect of MAO-B Inhibitors on Novel ObjectRecognition Rationale

Novel Object Recognition (NOR) is an assay of recognition learning andmemory retrieval, and it takes advantage of the spontaneous preferenceof rodents to investigate a novel object compared with a familiar one.It is an ethologically relevant task, which in contrast to fearconditioning, does not result from negative reinforcement (footshock)(e.g., Ennaceur and Delacour, Behav. Brain Res. 1988, 31, 47-59).

The NOR test has been employed extensively to assess the potentialcognitive-enhancing properties of novel compounds derived fromhigh-throughput screening. Object recognition the task relies on thenatural curiosity of rodents to explore novel objects in theirenvironments more than familiar ones. Obviously, for an object to be“familiar,” the animal must have attended to it before and rememberedthat experience. Hence, animals with better memory will attend andexplore a new object more than an object familiar to them. Duringtesting, the animal is presented with the training object and a second,novel one. Memory of the training object renders it familiar to theanimal, and it then spends more time exploring the new novel objectrather than the familiar one (Bourtchouladze et. al., Proc. Natl. Acad.Sci. USA 2003, 100, 10518-10522).

Neuroimaging, pharmacological, and lesion studies have demonstrated thatthe hippocampus and adjacent perirhinal cortex are critical for objectrecognition memory in rodents, monkeys, and humans (e.g., Mitchell,Behav. Brain Res. 1998, 97, 107-113; Teng et al., J. Neurosci. 2000, 20,3853-3863; Mumby, Brain Res. 2001, 127, 159-181; Eichenbaum et al.,Annu. Rev. Neurosci. 2007, 30, 127-152; Squire et al., Nat. Rev.Neurosci. 2007, 8, 872-883; and Vann and Alabasser, Curr. Opin.Neurobiol. 2011, 21, 440-445). Hence, object recognition provides anexcellent behavioral model to evaluate drug-compound effects oncognitive tasks associated with function of the hippocampus and cortex.

Procedures

Object recognition was tested in young adult mice and rats using thefollowing protocol. Animals are briefly handled by the experimenter 2-5days prior to training. Each compound was administered between 15minutes and 24-hours prior to, or following, training. Habituationsessions (duration 1-20 min, over 1-3 days) were conducted tofamiliarize the animal to the arena. During training trials (duration of1-20 min) the animals were allowed to explore two identical objects. Atest trial (duration of 1-20 min) was then performed 1-96 hrs later.

For novel object recognition, one object is replaced with one that isnovel. All combinations and locations of objects are used in a balancedmanner to reduce potential biases attributable to preference forparticular locations or objects. Training and test trials are recordedand scored by video-tracking software (e.g. Noldus Ethovision). Ananimal is scored as exploring an object when its head was orientedtoward the object within a distance of 1 cm (rat)/2 cm (mouse) or whenthe nose is touching the object. Turning around, climbing, or sitting onan object was not considered as exploration. If the animal generates along-term memory for the familiar object, it will spend significantlymore time exploring the novel object compared to the familiar objectduring the retention test (Cognitive enhancers are therefore expected tofacilitate this discrimination between the familiar and novel object).

A discrimination index was calculated as previously described(Bourtchouladze et al., Proc. Natl. Acad. Sci. USA 2003, 100,10518-10522). In each experiment, the experimenter was unaware (blind)to the treatment of the subjects during training and testing. Data wereanalyzed by one-way ANOVA with appropriate post-hoc tests using GraphPadPrism software package.

Results

Exemplary compounds of Formula (I) were found to significantly enhance24 hour memory. Significant effects were seen at several concentrations,including 1.0 mg/kg and 3 mg/kg. Control experiments showed thatcompound administration did not significantly affect the cumulativedistance traveled or amount of time spent exploring the left and righthalves of the box.

Taken together, these results show that MAO-B is a negative regulator ofmemory formation in the hippocampus, a temporal lobe structure that iscritical to memory formation in rodents as well as in humans.Importantly, MAO-B siRNA has been previously shown to induce a ‘gain offunction’ (that is, enhancement of contextual and temporal memoryformation). Hence these results confirm that MAO-B is a valid target forenhancing cognition, and memory specifically.

The specification, including the examples, is intended to be exemplaryonly, and it will be apparent to those skilled in the art that variousmodifications and variations can be made in the present inventionwithout departing from the scope or spirit of the invention as definedby the appended claims.

Furthermore, while certain details in the present disclosure areprovided to convey a thorough understanding of the invention as definedby the appended claims, it will be apparent to those skilled in the artthat certain embodiments may be practiced without these details.Moreover, in certain instances, well-known methods, procedures, or otherspecific details have not been described to avoid unnecessarilyobscuring aspects of the invention defined by the appended claims.

What is claimed is:
 1. A chemical entity, wherein the chemical entity isselected from the group consisting of compounds of Formula (I) andpharmaceutically acceptable salts of compounds of Formula (I)

wherein: n is 1 or 2; Y is CH or N; R¹ is a pyridine substituted with—CF₃, or phenyl substituted only in the meta and para positions with atotal of one, two, or three R^(a) members; each R^(a) is independentlyselected from the group consisting of halo, —C₁₋₄alkyl, —CF₃, —NO₂, and—OC₁₋₄alkyl; R² is selected from the group consisting of —C(R^(b))₂R^(c)or —CO—R^(d); each R^(b) is independently selected from the groupconsisting of —H, —F, and —C₁₋₃alkyl, or optionally two R^(b) membersare taken together with the carbon to which they are attached to form aC₃₋₆cycloalkyl ring; R^(c) is selected from the group consisting of —F,—NH₂, —OH, —OC₁₋₃alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and—C(CH₃)₂OH; provided that when at least one R^(b) is —F then R^(c) isnot —F; R^(d) is selected from the group consisting of —CH₃,—OC₁₋₄alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂; each R^(e) isindependently —H or —CH₃; and R³ is selected from the group consistingof —H, —CH₃, —OH, and —CF₃.
 2. A chemical entity as in claim 1, whereinn is
 1. 3. A chemical entity as in claim 1, wherein n is
 2. 4. Achemical entity as in claim 1, wherein Y is CH.
 5. A chemical entity asin claim 1, wherein Y is N.
 6. A chemical entity as in claim 1, whereinR¹ is 2-(trifluoromethyl)pyridin-4-yl or6-(trifluoromethyl)pyridin-2-yl.
 7. A chemical entity as in claim 1,wherein R¹ is phenyl substituted only in the meta and para positionswith a total of, two, or three R^(a) members independently selected fromthe group consisting of halo, —CF₃, —CH₃, —OCH₃, and —NO₂.
 8. A chemicalentity as in claim 1, wherein R¹ is selected from the group consistingof 3-chlorophenyl, 3-fluorophenyl, 3-nitrophenyl, 3-methylphenyl,3-methoxyphenyl, 3-(trifluoromethyl)phenyl, 3-chloro-4-fluorophenyl,3,4-difluorophenyl, 3-chloro-5-fluorophenyl, 3,5-difluorophenyl,3-fluoro-5-(trifluoromethyl)phenyl, 3,4,5-trifluorophenyl,4-chlorophenyl, 4-fluorophenyl, 4-trifluoromethyl)phenyl,4-fluoro-3-(trifluoromethyl)phenyl, 4-nitrophenyl, 4-methoxyphenyl,2-(trifluoromethyl)pyridin-4-yl, and 6-(trifluoromethyl)pyridin-2-yl. 9.A chemical entity as in claim 1, wherein R² is —(CR^(b))₂R^(c).
 10. Achemical entity as in claim 1, wherein R^(b) is independently selectedfrom the group consisting of —H, —F and —CH₃.
 11. A chemical entity asin claim 1, wherein two R^(b) members are taken together with the carbonto which they are attached to form a cyclopropyl, cyclobutyl,cyclopentyl, or cyclohexyl ring.
 12. A chemical entity as in claim 1,wherein R^(c) is selected from the group consisting of —F, —NH₂, —OH,—OCH₃, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and —C(CH₃)₂OH.
 13. Achemical entity as in claim 1, wherein R² is selected from the groupconsisting of —CH₂NH₂, —CH₂OH, —CH₂CH₂OH, —CH₂OCH₃, —CH₂CN,—CH₂(C═O)OCH₃, —CH₂(C═O)OCH₂CH₃, —CH₂(C═O)NH₂, —CH₂(CH₃)₂OH, —CH(OH)CH₃,—C(CH₃)₂OH, —C(CH₃)₂CH₂OH, —C(CH₃)₂(C═O)NH₂, —OCH₂CH₃, and —CF(CH₃)₂.14. A chemical entity as in claim 1, wherein R² is —CO—R^(d).
 15. Achemical entity as in claim 1, wherein R^(d) is selected from the groupconsisting of —CH₃, —OC₁₋₄alkyl, —NH₂, —NH(CH₃), —NHCH₂CH₂NH(CH₃) and—NHCH₂CH₂N(CH₃)₂.
 16. A chemical entity as in claim 1, wherein R² isselected from the group consisting of —(C═O)CH₃, —C(═O)OCH₃,—C(═O)OCH₂CH₃, —(C═O)NH₂, —(C═O)NHCH₃, —(C═O)N(CH₃)₂, —C═O)NHCH₂CH₂NH₂,—(C═O)NHCH₂CH₂NHCH₃, and —(C═O)NHCH₂CH₂N(CH₃)₂.
 17. A chemical entity asin claim 1, wherein R³ is H or —CH₃.
 18. A chemical entity as in claim1, wherein R³ is —CF₃ or —OH.
 19. A chemical entity selected from thegroup consisting of: Ethyl7-[(4-chlorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-[(3-fluorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-((3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-methylbenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-methylbenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-methoxybenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-methoxybenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-nitrobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-fluoro-3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate;Ethyl7-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate;Ethyl 7-((3,4-difluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3,5-difluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3,4,5-trifluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-chloro-4-fluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-nitrobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-chloro-5-fluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-chlorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-((3-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-((3-chloro-4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-(3-fluorophenethoxyl)quinoline-3-carboxylate; Ethyl7-(3-chlorophenethoxyl)quinoline-3-carboxylate; Methyl7-((3-chlorobenzyl)oxy)quinoline-3-carboxylate;2-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)propan-2-ol;2-(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)propan-2-ol;2-(7((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)propan-2-ol;2-(7-((4-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;2-(7-((3-Chlorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;2-(7-((3-Chloro-4-fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;2-(7-((3-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanol;(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)methanol;(7-((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)methanol;2-(7-(3-Fluorophenethoxyl)quinolin-3-yl)propan-2-ol;2-(7-(3-Chlorophenethoxyl)quinolin-3-yl)propan-2-ol;7-((3-Chlorobenzyl)oxy)-3-(methoxymethyl)quinoline;7-((4-Fluorobenzyl)oxy)-3-(2-fluoropropan-2-yl)quinoline;1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanone;1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol;(R)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol;(S)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol;7-((3-Chlorobenzyl)oxy)-N-methylquinoline-3-carboxamide;N-(2-Aminoethyl)-7-((3-chlorobenzyl)oxy)quinoline-3-carboxamide;7-((3-Chlorobenzyl)oxy)-N-(2-(methylamino)ethyl)quinoline-3-carboxamide;7-((3-Chlorobenzyl)oxy)-N-(2-(dimethylamino)ethyl)quinoline-3-carboxamide;(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanamine;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide; Ethyl2-(7-((3-fluorobenzyl)oxy)quinolin-3-yl)acetate; Ethyl2-(7((4-fluorobenzyl)oxy)quinolin-3-yl)acetate; Methyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)ethanol;2-(7-((3-Fluorobenzyl)oxy)quinolin-3-yl)acetamide;2-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)acetamide; Ethyl2-(7((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate;2-(7((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-1-ol;2-(7((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanamide;2-(7-((2-(Trifluoromethyl)pyridin-4-yl)methoxy)quinolin-3-yl)acetamide;1-(7((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-2-ol;7-((3-Chlorobenzyl)oxy)quinoline-3-carboxamide;2-{7-[(4-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;7-[(4-Fluorophenyl)methoxy]-3-(2-hydroxypropan-2-yl)quinolin-1-ium-1-olate;7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide;7-((4-Fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide;7-((3-Chlorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide;7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide;7-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide;7-[(3-Chlorophenyl)methoxy]-N-methyl-1,5-naphthyridine-3-carboxamide;(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol;2-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}acetonitrile;3-[(4-Fluorophenyl)methoxy]-7-(2-fluoropropan-2-yl)-1,5-naphthyridine;2-{7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-{7-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-{7-[(3-Chlorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamide;2-(7-((6-(Trifluoromethyl)pyridin-2-yl)methoxy)-1,5-naphthyridin-3-yl)acetamide;2-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide;2-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetamide; andpharmaceutically acceptable salts thereof.
 20. A pharmaceuticalcomposition comprising an effective amount of at least one chemicalentity selected from the compounds of Formula (I),

wherein: n is 1 or 2; Y is CH or N; R¹ is a pyridine substituted with—CF₃, or phenyl substituted only in the meta and para positions with atotal of one, two, or three R^(a) members; each R^(a) is independentlyselected from the group consisting of halo, —C₁₋₄alkyl, CF₃, —NO₂, and—OC₁₋₄alkyl; R² is selected from the group consisting of —C(R^(b))₂R^(c)or —CO—R^(d); each R^(b) is independently selected from the groupconsisting of —H, —F, and —C₁₋₃alkyl, or optionally two R^(b) membersare taken together with the carbon to which they are attached to form aC₃₋₆cycloalkyl ring; R^(c) is selected from the group consisting of —F,—NH₂, —OH, —OC₁₋₃alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and—C(CH₃)₂OH; provided that when at least one R^(b) is —F then R^(c) isnot —F; R^(d) is selected from the group consisting of —CH₃,—OC₁₋₄alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂; each R^(e) isindependently —H or —CH₃; R³ is selected from the group consisting of—H, —CH₃, —OH, and —CF₃, and pharmaceutically acceptable salts ofcompounds of Formula (I).
 21. A pharmaceutical composition comprising aneffective amount of at least one chemical entity of claim
 1. 22. Apharmaceutical composition comprising an effective amount of at leastone chemical entity of claim
 19. 23. A method for modulating one or moremonoamine oxidase (MAO) enzymes, comprising exposing MAO-A or MAO-B toan effective amount of at least one chemical entity selected fromcompounds of Formula (I)

wherein: n is 1 or 2; Y is CH or N; R¹ is a pyridine substituted with—CF₃, or phenyl substituted only in the meta and para positions with atotal of one, two, or three R^(a) members; each R^(a) is independentlyselected from the group consisting of halo, —C₁₋₄alkyl, CF₃, —NO₂, and—OC₁₋₄alkyl; R² is selected from the group consisting of —C(R^(b))₂R^(c)or —CO—R^(d); each R^(b) is independently selected from the groupconsisting of —H, —F, and —C₁₋₃alkyl, or optionally two R^(b) membersare taken together with the carbon to which they are attached to form aC₃₋₆cycloalkyl ring; R^(c) is selected from the group consisting of —F,—NH₂, —OH, —OC₁₋₃alkyl, —CH₂OH, —CN, —CO₂—C₁₋₄alkyl, —CO—NHR^(e), and—C(CH₃)₂OH; provided that when at least one R^(b) is —F then R^(c) isnot —F; R^(d) is selected from the group consisting of —CH₃,—OC₁₋₄alkyl, —NHR^(e), and —NHCH₂CH₂N(R^(e))₂; each R^(e) isindependently —H or —CH₃; R³ is selected from the group consisting of—H, —CH₃, —OH, and —CF₃, and pharmaceutically acceptable salt ofcompounds of Formula (I).
 24. A method for modulating one or moremonoamine oxidase (MAO) enzymes, comprising exposing MAO-A or MAO-B toan effective amount of at least one chemical entity of claim
 19. 25. Themethod of claim 24, wherein said one or more MAO enzymes is in a humansubject.
 26. A chemical entity as in claim 19, wherein the chemicalentity is selected from the group consisting of: Ethyl7-[(4-chlorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-[(4-fluorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-[(3-chlorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-[(3-fluorophenyl)methoxy]quinoline-3-carboxylate; Ethyl7-((3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-methylbenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((4-methylbenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-methoxybenzyl)oxy)quinoline-3-carboxylate; and Ethyl7-((4-methoxybenzyl)oxy)quinoline-3-carboxylate.
 27. A chemical entityas in claim 19, wherein the chemical entity is selected from the groupconsisting of: Ethyl 7-((4-nitrobenzyl)oxy)quinoline-3-carboxylate;Ethyl7-((4-fluoro-3-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate;Ethyl7-((3-fluoro-5-(trifluoromethyl)benzyl)oxy)quinoline-3-carboxylate;Ethyl 7-((3,4-difluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3,5-difluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3,4,5-trifluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-chloro-4-fluorobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-nitrobenzyl)oxy)quinoline-3-carboxylate; Ethyl7-((3-chloro-5-fluorobenzyl)oxy)quinoline-3-carboxylate; and Ethyl7-((3-chlorobenzyl)oxy)-2-methylquinoline-3-carboxylate.
 28. A chemicalentity as in claim 19, wherein the chemical entity is selected from thegroup consisting of: Ethyl7-((3-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-((4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-((3-chloro-4-fluorobenzyl)oxy)-2-methylquinoline-3-carboxylate; Ethyl7-(3-fluorophenethoxyl)quinoline-3-carboxylate; Ethyl7-(3-chlorophenethoxyl)quinoline-3-carboxylate; Methyl7-((3-chlorobenzyl)oxy)quinoline-3-carboxylate;2-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)propan-2-ol;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)propan-2-ol;2-(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)propan-2-ol; and2-(7((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)propan-2-ol.
 29. Achemical entity as in claim 19, wherein the chemical entity is selectedfrom the group consisting of:2-(7-((4-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;2-(7-((3-Chlorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;2-(7-((3-Chloro-4-fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;2-(7-((3-Fluorobenzyl)oxy)-2-methylquinolin-3-yl)propan-2-ol;(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanol;(7-((3,5-Difluorobenzyl)oxy)quinolin-3-yl)methanol;(7-((3,4,5-Trifluorobenzyl)oxy)quinolin-3-yl)methanol;2-(7-(3-Fluorophenethoxy)quinolin-3-yl)propan-2-ol;2-(7-(3-Chlorophenethoxy)quinolin-3-yl)propan-2-ol; and7-((3-Chlorobenzyl)oxy)-3-(methoxymethyl)quinoline.
 30. A chemicalentity as in claim 19, wherein the chemical entity is selected from thegroup consisting of:7-((4-Fluorobenzyl)oxy)-3-(2-fluoropropan-2-yl)quinoline;1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanone;1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol;(R)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol;(S)-1-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)ethanol;7-((3-Chlorobenzyl)oxy)-N-methylquinoline-3-carboxamide;N-(2-Aminoethyl)-7-((3-chlorobenzyl)oxy)quinoline-3-carboxamide;7-((3-Chlorobenzyl)oxy)-N-(2-(methylamino)ethyl)quinoline-3-carboxamide;7-((3-Chlorobenzyl)oxy)-N-(2-(dimethylamino)ethyl)quinoline-3-carboxamide;and (7-((3-Chlorobenzyl)oxy)quinolin-3-yl)methanamine.
 31. A chemicalentity as in claim 19, wherein the chemical entity is selected from thegroup consisting of: 2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide;Ethyl 2-(7-((3-fluorobenzyl)oxy)quinolin-3-yl)acetate; Ethyl2-(7-((4-fluorobenzyl)oxy)quinolin-3-yl)acetate; Methyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)acetate;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)acetamide;2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)ethanol;2-(7-((3-Fluorobenzyl)oxy)quinolin-3-yl)acetamide;2-(7-((4-Fluorobenzyl)oxy)quinolin-3-yl)acetamide; Ethyl2-(7-((3-chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanoate; and2-(7((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-1-ol.
 32. Achemical entity as in claim 19, wherein the chemical entity is selectedfrom the group consisting of:2-(7-((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropanamide;2-(7-((2-(Trifluoromethyl)pyridin-4-yl)methoxy)quinolin-3-yl)acetamide;1-(7((3-Chlorobenzyl)oxy)quinolin-3-yl)-2-methylpropan-2-ol;7-((3-Chlorobenzyl)oxy)quinoline-3-carboxamide;2-{7-[(4-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;7-[(4-Fluorophenyl)methoxy]-3-(2-hydroxypropan-2-yl)quinolin-1-ium-1-olate;7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide;7-((4-Fluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide;7-((3-Chlorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide;7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridine-3-carboxamide;7-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridine-3-carboxamide;and7-[(3-Chlorophenyl)methoxy]-N-methyl-1,5-naphthyridine-3-carboxamide.33. A chemical entity as in claim 19, wherein the chemical entity isselected from the group consisting of:(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)methanol;2-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}acetonitrile;3-[(4-Fluorophenyl)methoxy]-7-(2-fluoropropan-2-yl)-1,5-naphthyridine;2-{7-[(3-Fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-{7-[(3,4-Difluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-{7-[(3-Chloro-4-fluorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-{7-[(3-Chlorophenyl)methoxy]-1,5-naphthyridin-3-yl}propan-2-ol;2-(7-((3,4-Difluorobenzyl)oxy)-1,5-naphthyridin-3-yl)acetamide;2-(7-((6-(Trifluoromethyl)pyridin-2-yl)methoxy)-1,5-naphthyridin-3-yl)acetamide;2-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2,3,4-tetrahydroquinolin-3-yl)acetamide;and 2-(7-((3-Chlorobenzyl)oxy)-2-oxo-1,2-dihydroquinolin-3-yl)acetamide.34. A chemical entity as in claim 1, wherein the chemical entity is acompound of Formula (I).
 35. A chemical entity as in claim 1, whereinthe chemical entity is a pharmaceutically acceptable salt of a compoundof Formula (I).